* 607343

SAL-LIKE 4; SALL4


Alternative titles; symbols

HSAL4


HGNC Approved Gene Symbol: SALL4

Cytogenetic location: 20q13.2     Genomic coordinates (GRCh38): 20:51,782,331-51,802,521 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
20q13.2 ?IVIC syndrome 147750 AD 3
Duane-radial ray syndrome 607323 AD 3

TEXT

Description

Sal-like genes encode putative zinc finger transcription factors. For background information on SALL genes, see SALL1 (602218).


Cloning and Expression

Kohlhase et al. (2002) determined that the SALL4 gene encodes a protein with 3 C2H2 double zinc finger domains of the SAL-type, the second of which has a single C2H2 zinc finger attached at its C-terminal end, as well as an N-terminal C2HC zinc finger motif typical for vertebrate SAL-like proteins. By Northern blot analysis, they detected expression of a 5.5-kb SALL4 transcript exclusively in adult testis. RT-PCR confirmed expression in adult testis and revealed faint SALL4 expression in ovary and spleen.

Kohlhase et al. (2002) cloned mouse Sall4. Northern blot analysis of adult mouse tissues detected a 5.0- to 5.5-kb transcript only in testis and ovary. In situ hybridization revealed widespread Sall4 expression in early mouse embryos. Expression was gradually confined to the head region and the primitive streak, and later there was prominent expression in the developing midbrain, branchial arches, limbs, and genital papilla.


Gene Function

Based on the identified mutations in the SALL4 gene that result in the Duane-radial ray syndrome (DRRS; 607323), Al-Baradie et al. (2002) suggested that the gene likely plays a critical role in abducens motoneuron development.

SALL4 is an oncofetal protein that is expressed in human fetal liver and silenced in the adult liver, but is reexpressed in a subgroup of patients that have hepatocellular carcinoma with unfavorable prognosis. Yong et al. (2013) screened specimens obtained from 179 patients with hepatocellular carcinoma (114550) from Singapore for the expression of SALL4. Gene expression analysis showed the enrichment of progenitor-like gene signatures with overexpression of proliferative and metastatic genes in SALL4-positive hepatocellular carcinomas. Yong et al. (2013) found that in a multivariate Cox regression model, SALL4 is an independent prognostic factor for overall survival (hazard ratio for death, 2.87; 95% CI, 1.09 to 7.52; p = 0.03) in the Singapore cohort and an independent predictor of both overall survival (hazard ratio for death, 1.52; 95% CI, 1.00-2.32; p = 0.05) and early recurrence (hazard ratio, 1.67; 95% CI, 1.11-2.51; p = 0.01) in the Hong Kong cohort. Loss-of-function studies confirmed the critical role of SALL4 in cell survival and tumorigenicity. Blocking SALL4-corepressor interactions released suppression of PTEN (601728) and inhibited tumor formation in xenograft models in vivo.

To help avoid additional risks associated with tumor biopsy in patients with SALL4-negative tumors, Hopkins et al. (2013) requested that Yong et al. (2013) determine the sensitivity and specificity of the serum alpha-fetoprotein level in predicting the SALL4 status of their hepatocellular carcinoma patients. Yong et al. (2013) replied that in the Hong Kong cohort of patients with hepatocellular carcinoma they observed a significant correlation between SALL4 mRNA expression and the serum alpha-fetoprotein level (p less than 0.001). The sensitivity and specificity of serum alpha-fetoprotein levels in predicting SALL4 expression in this cohort of 228 patients were calculated to be 66.7% and 68.4%, respectively. The data suggested that with a cutoff value of 100 ng per milliliter, a serum alpha-fetoprotein level of 100 ng per milliliter or more can identify 66.7% of patients with SALL4 mRNA expression. However, 31.6% of patients without SALL4 expression would be falsely identified as being positive for SALL4 expression. Yong et al. (2013) suggested that, to assess SALL4 expression without the need for patient biopsy specimens, a noninvasive assay to test serum SALL4 expression be developed.

Suzuki et al. (2013) asked of Yong et al. (2013) whether the unfavorable clinical outcome in high-SALL4 hepatocellular carcinoma is attributable to features of cholangiocarcinoma. Masuda et al. (2013) inquired whether reprogramming factors such as KLF5 or TBX3 could be involved in the pathogenesis of SALL4-related hepatocellular carcinoma, and if reexpression of SALL4 through hepatitis B infection has a role in upregulation of SALL4. Yong et al. (2013) replied that more studies would be necessary to address these queries.


Gene Structure

The SALL4 gene contains 4 exons (Kohlhase et al., 2002; Al-Baradie et al., 2002). Kohlhase et al. (2002) determined that the mouse Sall4 gene contains 4 exons.


Mapping

Kohlhase et al. (2002) noted that SALL4 had been localized to chromosome 20q13.13-q13.2 by Deloukas et al. (2001). Kohlhase et al. (2002) mapped the mouse Sall4 gene to chromosome 2H3.


Molecular Genetics

Duane-Radial Ray Syndrome

Duane-radial ray syndrome (DRRS; 607323) is an autosomal dominant disorder characterized by forearm malformations and the Duane ocular anomaly. There is variable presentation within and among reported families, as well as overlap of clinical features with other conditions, most notably Holt-Oram syndrome (HOS; 142900), a condition resulting from mutation of the TBX5 locus (601620), and Townes-Brocks syndrome (TBS; 107480), known to be caused by mutation in SALL1. Due to phenotypic overlap between some DRRS patients and those with Townes-Brocks syndrome, Kohlhase et al. (2002) postulated that DRRS may result from mutations in a member of the human SALL gene family. In affected members of 5 unrelated families with DRRS, Kohlhase et al. (2002) identified 5 different heterozygous mutations in the SALL4 gene (see, e.g., 607343.0001-607343.0003).

Al-Baradie et al. (2002) ascertained 3 pedigrees with DRRS and mapped their disease gene to a region of chromosome 20 containing the SALL4 gene. Mutation analysis of SALL4 in these 3 pedigrees revealed 1 nonsense (607343.0005) and 2 frameshift (607343.0004; 607343.0006) heterozygous mutations.

In studies of the molecular defect in the TBX5 gene in patients with HOS, Brassington et al. (2003) found mutations in the SALL4 gene in 2 patients referred to them with the diagnosis of HOS. In 1 of the 2 cases, Bamshad (2003) stated that the primary care physician reexamined the patient and noted the presence of ophthalmoplegia, making the diagnosis of Duane-radial ray syndrome. Furthermore, Bamshad (2003) had not considered kidney defects typical of HOS and the affected mother of the patient who was later diagnosed with Duane-radial ray syndrome had pelvic kidneys. Kohlhase (2003) suggested that the SALL4 mutation in the second 'HOS' case of Brassington et al. (2003) was actually a rare polymorphism, as it did not affect a functional domain, was not conserved between mouse and man, and the unaffected parent also carried the mutation. Kohlhase (2003) noted that Duane anomaly is not present in some cases of Duane-radial ray syndrome. Associated kidney anomalies, imperforate anus, ear and foot anomalies, and hearing loss all point to the diagnosis of Duane-radial ray syndrome. Kohlhase (2003) suggested that severe congenital heart defects, such as those observed in HOS, are not part of the Duane-radial ray syndrome.

Kohlhase et al. (2003) analyzed the SALL4 gene in families with patients with DRRS. They identified a novel SALL4 mutation (607343.0007) in 1 family in which the father was originally thought to have thalidomide embryopathy and had a daughter with a similar phenotype. They also found 2 novel mutations in 2 German families originally diagnosed with Holt-Oram syndrome and a further mutation in 1 of 2 families carrying the diagnosis of 'acrorenoocular syndrome,' which is the same entity as DRRS (607343.0008-607343.0009).

In 6 families with Duane-radial ray syndrome in whom no point mutation in the SALL4 gene could be identified, Borozdin et al. (2004) performed segregation analysis of intragenic SNPs to detect loss of heterozygosity, consistent with an intragenic deletion of the gene. Using this method, heterozygous deletion of at least exon 2 of the SALL4 gene was suggested in 4 of the 6 families. Quantitative RT-PCR demonstrated that 2 families had deletion of all 4 exons (see 607343.0010), 2 had deletion of exons 1-3, 1 was heterozygous for a deletion of exon 4, and 1 had a deletion of 8.9 kb, including exon 1. One of the families had been reported by MacDermot and Winter (1987). These deletions occurred de novo in 2 sporadic cases, and segregated with the phenotype in the remaining families. Borozdin et al. (2004) concluded that, in contrast to the likely dominant-negative action of SALL1 mutations (602218) causing Townes-Brocks syndrome, Duane-radial ray syndrome is clearly the result of SALL4 haploinsufficiency.

Kohlhase et al. (2005) stated that 22 different SALL4 mutations had been described, all of which lead to preterminal stop codons and are likely to be disease-causing via haploinsufficiency.

Miertus et al. (2006) reported the first missense mutation in the SALL4 gene (H888R; 607343.0012) in a patient with a mild form of Duane-radial ray syndrome and cranial midline defects.

IVIC Syndrome

Paradisi and Arias (2007) identified a heterozygous mutation in the SALL4 gene (607343.0013) in 14 affected members of a large Venezuelan family with the IVIC syndrome (IVIC; 147750). Affected members showed wide phenotypic variability, similar to that seem in other SALL4-related disorders.


Animal Model

Human mutations in TBX5 (601620), a gene encoding a T-box transcription factor, and SALL4, a gene encoding a zinc finger transcription factor, cause similar upper limb and heart defects. Mutations in SALL4 are responsible for the Duane-radial ray syndrome (607323); mutations in TBX5 are responsible for the Holt-Oram syndrome (142900). Koshiba-Takeuchi et al. (2006) showed that Tbx5 regulates Sall4 expression in the developing mouse forelimb and heart; mice heterozygous for a gene trap allele of Sall4 showed limb and heart defects that modeled human disease. Tbx5 and Sall4 interacted both positively and negatively to finely regulate patterning and morphogenesis of the anterior forelimb and heart. Thus, a positive and negative feed-forward circuit between Tbx5 and Sall4 ensures precise patterning of embryonic limb and heart and provides a unifying mechanism for heart/hand syndromes.


ALLELIC VARIANTS ( 13 Selected Examples):

.0001 DUANE-RADIAL RAY SYNDROME

SALL4, GLN652TER
  
RCV000003482

Collins et al. (1993) described a 3-generation family with Duane anomaly and thenar hypoplasia, or Duane-radial ray syndrome (DRRS; 607323). In this family, Kohlhase et al. (2002) demonstrated heterozygosity for a 1954C-T transition in the SALL4 gene in affected individuals, resulting in a gln652-to-ter (Q652X) mutation. The resultant protein was predicted to lack the third (carboxy-terminal) double zinc finger domain.


.0002 DUANE-RADIAL RAY SYNDROME

SALL4, 1-BP DEL, 1053G
  
RCV000003483

In a 3-generation family with Duane-ray radial syndrome (DRRS; 607323), Kohlhase et al. (2002) demonstrated heterozygosity for a 1053G deletion in the SALL4 gene in affected individuals. The mutation was predicted to result in a truncated protein lacking all 3 double zinc finger motifs.


.0003 DUANE-RADIAL RAY SYNDROME

SALL4, 1-BP INS, 940C
  
RCV000003484

In an individual with Duane-radial ray syndrome (DRRS; 607323), anal stenosis, and deafness, Kohlhase et al. (2002) demonstrated heterozygosity for a cytosine insertion between bases 940 and 941 in the SALL4 gene. The mutation was predicted to result in a truncated protein lacking all 3 double zinc finger motifs.


.0004 DUANE-RADIAL RAY SYNDROME

SALL4, 1-BP DEL, 1904T
  
RCV000003485

In a family in which 8 individuals had Duane-radial ray syndrome (DRRS; 607323), Al-Baradie et al. (2002) identified a heterozygous 1-bp deletion, 1904delT, predicted to result in a frameshift leading to a stop codon after 4 altered amino acids. Six of the affected individuals had bilateral or unilateral Duane syndrome type 1 (see 126800); they showed marked or complete limitation of abduction with minimal or no limitation of adduction. The other 2 affected individuals had Duane syndrome type 3; they showed marked or complete limitation of both abduction and adduction. Seven had bilateral or unilateral thenar hypoplasia. A thumb defect was present in 6. Absent radial pulse, unilateral or bilateral, was noted in 5. Club wrist and short forearm were present in several, as well as shoulder dislocation. Only 1 of the 8 affected members had sensorineural hearing loss.


.0005 DUANE-RADIAL RAY SYNDROME

SALL4, ARG865TER
  
RCV000003486...

In affected members of a family with Duane-radial ray syndrome (DRRS; 607323) originally reported by Okihiro et al. (1977), Al-Baradie et al. (2002) found heterozygosity for a 2593C-T change in exon 3 of the SALL4 gene, resulting in an arg-to-ter (R865X) substitution.

Kohlhase et al. (2003) identified the R865X mutation in affected members of family 1 reported by Becker et al. (2002) as having an overlapping phenotype of Okihiro and acrorenoocular syndromes. The proband had bilateral Duane anomaly, bilateral absent thumbs, absent radii, and shortened humeri. She also had slightly dysplastic optic discs and mild bilateral conductive hearing loss. Her affected mother had absent thumbs, shortened forearms, sensorineural hearing loss, and hypoplastic dystopic left kidney.


.0006 DUANE-RADIAL RAY SYNDROME

SALL4, 1-BP DEL, 2425G
  
RCV000003487

In a family in which 3 members had Duane-radial ray syndrome (DRRS; 607323), Al-Baradie et al. (2002) found heterozygosity for a 1-bp deletion, 2425delG, in exon 2 of the SALL4 gene. The deletion was predicted to result in a frameshift leading to a stop codon after 46 altered amino acids. Two of the affected individuals had Duane syndrome type 1 (see 126800), and all 3 had bilateral thumb defects. One had sensorineural hearing loss.


.0007 DUANE-RADIAL RAY SYNDROME

SALL4, 1-BP DEL, 326C
  
RCV000003488

McBride and Read (1994) described a family in which thalidomide embryopathy was diagnosed in the father in childhood based on the nature of the abnormalities: bilateral thumb aplasia and hypoplastic radii in the presence of a history of possible exposure during pregnancy. His daughter was born with bilateral asymmetric radial ray defects consisting of absence of the thumb and first fingers, radial aplasia, and ulnar hypoplasia. Kohlhase et al. (2003) demonstrated a 1-bp deletion in exon 2 of the SALL4 cDNA, 326delC, in the father and daughter. Whereas the initial diagnosis was Holt-Oram syndrome (142900), on reexamination the finding of bilateral Duane anomaly caused revision of the diagnosis to Okihiro syndrome, also known as Duane-radial ray syndrome (607323). This family had been described by McBride and Read (1994) as a possible example of thalidomide mutagenicity.


.0008 DUANE-RADIAL RAY SYNDROME

SALL4, LYS175TER
  
RCV000003489

In a patient with sporadic Duane-radial ray syndrome (DRRS; 607323), Kohlhase et al. (2003) identified a heterozygous 523A-T transversion in exon 2 of the SALL4 gene, resulting in a lys175-to-ter (K175X) substitution. The patient had radial abnormalities, persistent foramen ovale, crossed dystopia of the kidneys, and bilateral Duane anomaly. He also had mild epicanthal folds and a broad, flat nasal bridge.


.0009 DUANE-RADIAL RAY SYNDROME

SALL4, ARG617TER
  
RCV000003490

In a father and daughter with Duane-radial ray syndrome (DRRS; 607323), Kohlhase et al. (2003) identified a heterozygous 1849C-T transition in exon 2 of the SALL4 gene, resulting in an arg617-to-ter (R617X) substitution. The daughter had bilateral thumb aplasia and radial club hands with shortened arms. She also had ventricular septal defect, hypertelorism with slight epicanthal folds, and flat feet with sandal gaps and broad, short first toes. She had no renal anomalies and no Duane anomaly. The father had less severe limb malformations, flat feet with sandal gaps, and horseshoe kidney. The initial diagnosis was Holt-Oram syndrome (142900), but the finding of Duane anomaly in the father confirmed Duane-radial ray syndrome.


.0010 DUANE-RADIAL RAY SYNDROME

SALL4, DEL
   RCV000003491

In affected members of family 2 reported by Becker et al. (2002) as having an overlapping phenotype of Okihiro and acrorenoocular syndromes (DRRS; 607323), Borozdin et al. (2004) identified a heterozygous deletion of at least 135 kb, including the entire SALL4 gene.


.0011 DUANE-RADIAL RAY SYNDROME

SALL4, ARG905TER
  
RCV000003492...

In 6 affected members of a family with Duane-radial ray syndrome (DRRS; 607323), Terhal et al. (2006) identified a heterozygous 2713C-T transition in the SALL4 gene, resulting in an arg905-to-ter (R905X) substitution. The truncated protein was predicted to lack the most C-terminal part of the protein including half of the second zinc finger within the most C-terminal double zinc finger domain. The mutant protein probably escapes nonsense-mediated mRNA decay and may retain some residual function. The phenotype in this family was highly variable; only 1 patient had the full syndrome, whereas other family members had only a subset of anomalies.


.0012 DUANE-RADIAL RAY SYNDROME

SALL4, HIS888ARG
  
RCV000003493

In an Italian child with a mild form of Duane-radial ray syndrome (DRRS; 607323) who was originally reported by Parentin and Perissutti (2003), Miertus et al. (2006) identified a heterozygous 2663A-G transition in exon 3 of the SALL4 gene, resulting in a his888-to-arg (H888R) substitution in a highly conserved region within the N-terminal ZF motif of the most C-terminal double ZF domain of the protein. The mutation was present in the affected father and maternal grandmother, but not in the unaffected mother or twin sister of the proband. The proband had mild features of Duane-radial ray syndrome as well as cranial midline defects, including facial dysmorphism, pituitary hypoplasia, and a single central incisor. Molecular modeling predicted that the H888R substitution does not result in loss of zinc binding but leads to increased DNA-binding affinity of the domain. Miertus et al. (2006) noted that this was the first reported missense mutation in the SALL4 gene.


.0013 IVIC SYNDROME (1 family)

SALL4, 1-BP DEL, 2607A
  
RCV000003494

In 14 affected members of a large Venezuelan family with IVIC syndrome (IVIC; 147750), originally reported by Arias et al. (1980), Paradisi and Arias (2007) identified a heterozygous 1-bp deletion (2607delA) in exon 3 of the SALL4 gene, resulting in a truncated protein. The mutated mRNA was predicted to escape nonsense-mediated decay because of its location. There was wide intrafamilial phenotypic variability.


REFERENCES

  1. Al-Baradie, R., Yamada, K., St. Hilaire, C., Chan, W.-M., Andrews, C., McIntosh, N., Nakano, M., Martonyi, E. J., Raymond, W. R., Okumura, S., Okihiro, M. M., Engle, E. C. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am. J. Hum. Genet. 71: 1195-1199, 2002. [PubMed: 12395297, images, related citations] [Full Text]

  2. Arias, S., Penchaszadeh, V. B., Pinto-Cisternas, J., Larrauri, S. The IVIC syndrome: a new autosomal dominant complex pleiotropic syndrome with radial ray hypoplasia, hearing impairment, external ophthalmoplegia, and thrombocytopenia. Am. J. Med. Genet. 6: 25-29, 1980. [PubMed: 7395922, related citations] [Full Text]

  3. Bamshad, M. J. Personal Communication. Salt Lake City, Utah 6/26/2003.

  4. Becker, K., Beales, P. L., Calver, D. M., Matthijs, G., Mohammed, S. N. Okihiro syndrome and acro-renal-ocular syndrome: clinical overlap, expansion of the phenotype, and absence of PAX2 mutations in two new families. J. Med. Genet. 39: 68-71, 2002. [PubMed: 11826030, related citations] [Full Text]

  5. Borozdin, W., Boehm, D., Leipoldt, M., Wilhelm, C., Reardon, W., Clayton-Smith, J., Becker, K., Muhlendyck, H., Winter, R., Giray, O., Silan, F., Kohlhase, J. SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechanism. J. Med. Genet. 41: e113, 2004. Note: Electronic Article. [PubMed: 15342710, related citations] [Full Text]

  6. Brassington, A.-M. E., Sung, S. S., Toydemir, R. M., Le, T., Roeder, A. D., Rutherford, A. E., Whitby, F. G., Jorde, L. B., Bamshad, M. J. Expressivity of Holt-Oram syndrome is not predicted by TBX5 genotype. Am. J. Hum. Genet. 73: 74-85, 2003. [PubMed: 12789647, images, related citations] [Full Text]

  7. Collins, A., Baraitser, M., Pembrey, M. Okihiro syndrome: thenar hypoplasia and Duane anomaly in three generations. Clin. Dysmorph. 2: 237-240, 1993. [PubMed: 8287186, related citations]

  8. Deloukas, P., Matthews, L. H., Ashurst, J., Burton, J., Gilbert, J. G. R., Jones, M., Stavrides, G., Almeida, J. P., Babbage, A. K., Bagguley, C. L., Bailey, J., Barlow, K. F., and 115 others. The DNA sequence and comparative analysis of human chromosome 20. Nature 414: 865-871, 2001. [PubMed: 11780052, related citations] [Full Text]

  9. Hopkins, L. J., Rowe, I. A. C., Houlihan, D. D. Comment on 'Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.' (Letter) New Eng. J. Med. 369: 1170 only, 2013. [PubMed: 24047069, related citations] [Full Text]

  10. Kohlhase, J., Chitayat, D., Kotzot, D., Ceylaner, S., Froster, U. G., Fuchs, S., Montgomery, T., Rosler, B. SALL4 mutations in Okihiro syndrome (Duane-radial ray syndrome), acro-renal-ocular syndrome, and related disorders. Hum. Mutat. 26: 176-183, 2005. [PubMed: 16086360, related citations] [Full Text]

  11. Kohlhase, J., Heinrich, M., Liebers, M., Archangelo, L. F., Reardon, W., Kispert, A. Cloning and expression analysis of Sall4, the murine homologue of the gene mutated in Okihiro syndrome. Cytogenet. Genome Res. 98: 274-277, 2002. [PubMed: 12826753, related citations] [Full Text]

  12. Kohlhase, J., Heinrich, M., Schubert, L., Liebers, M., Kispert, A., Laccone, F., Turnpenny, P., Winter, R. M., Reardon, W. Okihiro syndrome is caused by SALL4 mutations. Hum. Molec. Genet. 11: 2979-2987, 2002. [PubMed: 12393809, related citations] [Full Text]

  13. Kohlhase, J., Schubert, L., Liebers, M., Rauch, A., Becker, K., Mohammed, S. N., Newbury-Ecob, R., Reardon, W. Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy. J. Med. Genet. 40: 473-478, 2003. [PubMed: 12843316, related citations] [Full Text]

  14. Kohlhase, J. Personal Communication. Goettingen, Germany 7/16/2003.

  15. Koshiba-Takeuchi, K., Takeuchi, J. K., Arruda, E. P., Kathiriya, I. S., Mo, R., Hui, C., Srivastava, D., Bruneau, B. G. Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart. Nature Genet. 38: 175-183, 2006. [PubMed: 16380715, related citations] [Full Text]

  16. MacDermot, K. D., Winter, R. M. Radial ray defect and Duane anomaly: report of a family with autosomal dominant transmission. Am. J. Med. Genet. 27: 313-319, 1987. [PubMed: 3605217, related citations] [Full Text]

  17. Masuda, S., Suzuki, K., Izpisua Belmonte, J. C. Comment on 'Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.' (Letter) New Eng. J. Med. 369: 1171 only, 2013. [PubMed: 24047071, related citations] [Full Text]

  18. McBride, W. G., Read, A. P. Thalidomide may be a mutagen. (Letter) Brit. Med. J. 308: 1635-1636, 1994. [PubMed: 8025439, related citations] [Full Text]

  19. Miertus, J., Borozdin, W., Frecer, V., Tonini, G., Bertok, S., Amoroso, A., Miertus, S., Kohlhase, J. A SALL4 zinc finger missense mutation predicted to result in increased DNA binding affinity is associated with cranial midline defects and mild features of Okihiro syndrome. Hum. Genet. 119: 154-161, 2006. [PubMed: 16402211, related citations] [Full Text]

  20. Okihiro, M. M., Tasaki, T., Nakano, K. K., Bennett, B. K. Duane syndrome and congenital upper-limb anomalies: a familial occurrence. Arch. Neurol. 34: 174-179, 1977. [PubMed: 843249, related citations] [Full Text]

  21. Paradisi, I., Arias, S. IVIC syndrome is caused by a c.2607delA mutation in the SALL4 locus. Am. J. Med. Genet. 143A: 326-332, 2007. [PubMed: 17256792, related citations] [Full Text]

  22. Parentin, F., Perissutti, P. Solitary median maxillary central incisor, Duane retraction syndrome, growth hormone deficiency and duplicated thumb phalanx: a case report. Clin. Dysmorph. 12: 141-142, 2003. [PubMed: 12868480, related citations] [Full Text]

  23. Suzuki, E., Chiba, T., Yokosuka, O. Comment on 'Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.' (Letter) New Eng. J. Med. 369: 1170-1171, 2013. [PubMed: 24047070, related citations] [Full Text]

  24. Terhal, P., Rosler, B., Kohlhase, J. A family with features overlapping Okihiro syndrome, hemifacial microsomia and isolated Duane anomaly caused by a novel SALL4 mutation. Am. J. Med. Genet. 140A: 222-226, 2006. [PubMed: 16411190, related citations] [Full Text]

  25. Yong, K. J., Chai, L., Tenen, D. G. Reply to comments on 'Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.' (Letter) New Eng. J. Med. 369: 1172-1173, 2013. [PubMed: 24047073, related citations] [Full Text]

  26. Yong, K. J., Gao, C., Lim, J. S. J., Yan, B., Yang, H., Dimitrov, T., Kawasaki, A., Ong, C. W., Wong, K.-F., Lee, S., Ravikumar, S., Srivastava, S., Tian, X., Poon, R. T., Fan, S. T., Luk, J. M., Dan, Y. Y., Salto-Tellez, M., Chai, L., Tenen, D. G. Oncofetal gene SALL4 in aggressive hepatocellular carcinoma. New Eng. J. Med. 368: 2266-2276, 2013. [PubMed: 23758232, images, related citations] [Full Text]


Ada Hamosh - updated : 10/23/2013
Ada Hamosh - updated : 7/1/2013
Cassandra L. Kniffin - updated : 3/26/2007
Cassandra L. Kniffin - updated : 5/16/2006
Cassandra L. Kniffin - updated : 2/9/2006
Victor A. McKusick - updated : 2/7/2006
Cassandra L. Kniffin - updated : 1/3/2006
Victor A. McKusick - updated : 12/27/2005
Cassandra L. Kniffin - updated : 7/6/2005
Victor A. McKusick - updated : 10/12/2004
Victor A. McKusick - updated : 1/9/2004
Patricia A. Hartz - updated : 9/4/2003
Victor A. McKusick - updated : 8/1/2003
Victor A. McKusick - updated : 12/23/2002
Creation Date:
George E. Tiller : 11/13/2002
carol : 06/10/2021
carol : 03/26/2020
carol : 10/19/2016
carol : 04/13/2016
alopez : 10/23/2013
alopez : 10/23/2013
alopez : 7/1/2013
wwang : 4/16/2009
wwang : 4/2/2007
ckniffin : 3/26/2007
wwang : 5/18/2006
ckniffin : 5/16/2006
wwang : 2/13/2006
ckniffin : 2/9/2006
terry : 2/7/2006
wwang : 1/9/2006
ckniffin : 1/3/2006
alopez : 12/28/2005
terry : 12/27/2005
terry : 12/20/2005
carol : 7/7/2005
ckniffin : 7/6/2005
tkritzer : 10/20/2004
terry : 10/12/2004
alopez : 1/14/2004
terry : 1/9/2004
mgross : 9/4/2003
carol : 8/1/2003
carol : 1/10/2003
carol : 1/10/2003
tkritzer : 1/8/2003
terry : 12/23/2002
cwells : 11/14/2002
cwells : 11/14/2002

* 607343

SAL-LIKE 4; SALL4


Alternative titles; symbols

HSAL4


HGNC Approved Gene Symbol: SALL4

SNOMEDCT: 699867001, 720415006, 722019000;  


Cytogenetic location: 20q13.2     Genomic coordinates (GRCh38): 20:51,782,331-51,802,521 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
20q13.2 ?IVIC syndrome 147750 Autosomal dominant 3
Duane-radial ray syndrome 607323 Autosomal dominant 3

TEXT

Description

Sal-like genes encode putative zinc finger transcription factors. For background information on SALL genes, see SALL1 (602218).


Cloning and Expression

Kohlhase et al. (2002) determined that the SALL4 gene encodes a protein with 3 C2H2 double zinc finger domains of the SAL-type, the second of which has a single C2H2 zinc finger attached at its C-terminal end, as well as an N-terminal C2HC zinc finger motif typical for vertebrate SAL-like proteins. By Northern blot analysis, they detected expression of a 5.5-kb SALL4 transcript exclusively in adult testis. RT-PCR confirmed expression in adult testis and revealed faint SALL4 expression in ovary and spleen.

Kohlhase et al. (2002) cloned mouse Sall4. Northern blot analysis of adult mouse tissues detected a 5.0- to 5.5-kb transcript only in testis and ovary. In situ hybridization revealed widespread Sall4 expression in early mouse embryos. Expression was gradually confined to the head region and the primitive streak, and later there was prominent expression in the developing midbrain, branchial arches, limbs, and genital papilla.


Gene Function

Based on the identified mutations in the SALL4 gene that result in the Duane-radial ray syndrome (DRRS; 607323), Al-Baradie et al. (2002) suggested that the gene likely plays a critical role in abducens motoneuron development.

SALL4 is an oncofetal protein that is expressed in human fetal liver and silenced in the adult liver, but is reexpressed in a subgroup of patients that have hepatocellular carcinoma with unfavorable prognosis. Yong et al. (2013) screened specimens obtained from 179 patients with hepatocellular carcinoma (114550) from Singapore for the expression of SALL4. Gene expression analysis showed the enrichment of progenitor-like gene signatures with overexpression of proliferative and metastatic genes in SALL4-positive hepatocellular carcinomas. Yong et al. (2013) found that in a multivariate Cox regression model, SALL4 is an independent prognostic factor for overall survival (hazard ratio for death, 2.87; 95% CI, 1.09 to 7.52; p = 0.03) in the Singapore cohort and an independent predictor of both overall survival (hazard ratio for death, 1.52; 95% CI, 1.00-2.32; p = 0.05) and early recurrence (hazard ratio, 1.67; 95% CI, 1.11-2.51; p = 0.01) in the Hong Kong cohort. Loss-of-function studies confirmed the critical role of SALL4 in cell survival and tumorigenicity. Blocking SALL4-corepressor interactions released suppression of PTEN (601728) and inhibited tumor formation in xenograft models in vivo.

To help avoid additional risks associated with tumor biopsy in patients with SALL4-negative tumors, Hopkins et al. (2013) requested that Yong et al. (2013) determine the sensitivity and specificity of the serum alpha-fetoprotein level in predicting the SALL4 status of their hepatocellular carcinoma patients. Yong et al. (2013) replied that in the Hong Kong cohort of patients with hepatocellular carcinoma they observed a significant correlation between SALL4 mRNA expression and the serum alpha-fetoprotein level (p less than 0.001). The sensitivity and specificity of serum alpha-fetoprotein levels in predicting SALL4 expression in this cohort of 228 patients were calculated to be 66.7% and 68.4%, respectively. The data suggested that with a cutoff value of 100 ng per milliliter, a serum alpha-fetoprotein level of 100 ng per milliliter or more can identify 66.7% of patients with SALL4 mRNA expression. However, 31.6% of patients without SALL4 expression would be falsely identified as being positive for SALL4 expression. Yong et al. (2013) suggested that, to assess SALL4 expression without the need for patient biopsy specimens, a noninvasive assay to test serum SALL4 expression be developed.

Suzuki et al. (2013) asked of Yong et al. (2013) whether the unfavorable clinical outcome in high-SALL4 hepatocellular carcinoma is attributable to features of cholangiocarcinoma. Masuda et al. (2013) inquired whether reprogramming factors such as KLF5 or TBX3 could be involved in the pathogenesis of SALL4-related hepatocellular carcinoma, and if reexpression of SALL4 through hepatitis B infection has a role in upregulation of SALL4. Yong et al. (2013) replied that more studies would be necessary to address these queries.


Gene Structure

The SALL4 gene contains 4 exons (Kohlhase et al., 2002; Al-Baradie et al., 2002). Kohlhase et al. (2002) determined that the mouse Sall4 gene contains 4 exons.


Mapping

Kohlhase et al. (2002) noted that SALL4 had been localized to chromosome 20q13.13-q13.2 by Deloukas et al. (2001). Kohlhase et al. (2002) mapped the mouse Sall4 gene to chromosome 2H3.


Molecular Genetics

Duane-Radial Ray Syndrome

Duane-radial ray syndrome (DRRS; 607323) is an autosomal dominant disorder characterized by forearm malformations and the Duane ocular anomaly. There is variable presentation within and among reported families, as well as overlap of clinical features with other conditions, most notably Holt-Oram syndrome (HOS; 142900), a condition resulting from mutation of the TBX5 locus (601620), and Townes-Brocks syndrome (TBS; 107480), known to be caused by mutation in SALL1. Due to phenotypic overlap between some DRRS patients and those with Townes-Brocks syndrome, Kohlhase et al. (2002) postulated that DRRS may result from mutations in a member of the human SALL gene family. In affected members of 5 unrelated families with DRRS, Kohlhase et al. (2002) identified 5 different heterozygous mutations in the SALL4 gene (see, e.g., 607343.0001-607343.0003).

Al-Baradie et al. (2002) ascertained 3 pedigrees with DRRS and mapped their disease gene to a region of chromosome 20 containing the SALL4 gene. Mutation analysis of SALL4 in these 3 pedigrees revealed 1 nonsense (607343.0005) and 2 frameshift (607343.0004; 607343.0006) heterozygous mutations.

In studies of the molecular defect in the TBX5 gene in patients with HOS, Brassington et al. (2003) found mutations in the SALL4 gene in 2 patients referred to them with the diagnosis of HOS. In 1 of the 2 cases, Bamshad (2003) stated that the primary care physician reexamined the patient and noted the presence of ophthalmoplegia, making the diagnosis of Duane-radial ray syndrome. Furthermore, Bamshad (2003) had not considered kidney defects typical of HOS and the affected mother of the patient who was later diagnosed with Duane-radial ray syndrome had pelvic kidneys. Kohlhase (2003) suggested that the SALL4 mutation in the second 'HOS' case of Brassington et al. (2003) was actually a rare polymorphism, as it did not affect a functional domain, was not conserved between mouse and man, and the unaffected parent also carried the mutation. Kohlhase (2003) noted that Duane anomaly is not present in some cases of Duane-radial ray syndrome. Associated kidney anomalies, imperforate anus, ear and foot anomalies, and hearing loss all point to the diagnosis of Duane-radial ray syndrome. Kohlhase (2003) suggested that severe congenital heart defects, such as those observed in HOS, are not part of the Duane-radial ray syndrome.

Kohlhase et al. (2003) analyzed the SALL4 gene in families with patients with DRRS. They identified a novel SALL4 mutation (607343.0007) in 1 family in which the father was originally thought to have thalidomide embryopathy and had a daughter with a similar phenotype. They also found 2 novel mutations in 2 German families originally diagnosed with Holt-Oram syndrome and a further mutation in 1 of 2 families carrying the diagnosis of 'acrorenoocular syndrome,' which is the same entity as DRRS (607343.0008-607343.0009).

In 6 families with Duane-radial ray syndrome in whom no point mutation in the SALL4 gene could be identified, Borozdin et al. (2004) performed segregation analysis of intragenic SNPs to detect loss of heterozygosity, consistent with an intragenic deletion of the gene. Using this method, heterozygous deletion of at least exon 2 of the SALL4 gene was suggested in 4 of the 6 families. Quantitative RT-PCR demonstrated that 2 families had deletion of all 4 exons (see 607343.0010), 2 had deletion of exons 1-3, 1 was heterozygous for a deletion of exon 4, and 1 had a deletion of 8.9 kb, including exon 1. One of the families had been reported by MacDermot and Winter (1987). These deletions occurred de novo in 2 sporadic cases, and segregated with the phenotype in the remaining families. Borozdin et al. (2004) concluded that, in contrast to the likely dominant-negative action of SALL1 mutations (602218) causing Townes-Brocks syndrome, Duane-radial ray syndrome is clearly the result of SALL4 haploinsufficiency.

Kohlhase et al. (2005) stated that 22 different SALL4 mutations had been described, all of which lead to preterminal stop codons and are likely to be disease-causing via haploinsufficiency.

Miertus et al. (2006) reported the first missense mutation in the SALL4 gene (H888R; 607343.0012) in a patient with a mild form of Duane-radial ray syndrome and cranial midline defects.

IVIC Syndrome

Paradisi and Arias (2007) identified a heterozygous mutation in the SALL4 gene (607343.0013) in 14 affected members of a large Venezuelan family with the IVIC syndrome (IVIC; 147750). Affected members showed wide phenotypic variability, similar to that seem in other SALL4-related disorders.


Animal Model

Human mutations in TBX5 (601620), a gene encoding a T-box transcription factor, and SALL4, a gene encoding a zinc finger transcription factor, cause similar upper limb and heart defects. Mutations in SALL4 are responsible for the Duane-radial ray syndrome (607323); mutations in TBX5 are responsible for the Holt-Oram syndrome (142900). Koshiba-Takeuchi et al. (2006) showed that Tbx5 regulates Sall4 expression in the developing mouse forelimb and heart; mice heterozygous for a gene trap allele of Sall4 showed limb and heart defects that modeled human disease. Tbx5 and Sall4 interacted both positively and negatively to finely regulate patterning and morphogenesis of the anterior forelimb and heart. Thus, a positive and negative feed-forward circuit between Tbx5 and Sall4 ensures precise patterning of embryonic limb and heart and provides a unifying mechanism for heart/hand syndromes.


ALLELIC VARIANTS 13 Selected Examples):

.0001   DUANE-RADIAL RAY SYNDROME

SALL4, GLN652TER
SNP: rs74315424, ClinVar: RCV000003482

Collins et al. (1993) described a 3-generation family with Duane anomaly and thenar hypoplasia, or Duane-radial ray syndrome (DRRS; 607323). In this family, Kohlhase et al. (2002) demonstrated heterozygosity for a 1954C-T transition in the SALL4 gene in affected individuals, resulting in a gln652-to-ter (Q652X) mutation. The resultant protein was predicted to lack the third (carboxy-terminal) double zinc finger domain.


.0002   DUANE-RADIAL RAY SYNDROME

SALL4, 1-BP DEL, 1053G
SNP: rs1601170510, ClinVar: RCV000003483

In a 3-generation family with Duane-ray radial syndrome (DRRS; 607323), Kohlhase et al. (2002) demonstrated heterozygosity for a 1053G deletion in the SALL4 gene in affected individuals. The mutation was predicted to result in a truncated protein lacking all 3 double zinc finger motifs.


.0003   DUANE-RADIAL RAY SYNDROME

SALL4, 1-BP INS, 940C
SNP: rs1601170799, ClinVar: RCV000003484

In an individual with Duane-radial ray syndrome (DRRS; 607323), anal stenosis, and deafness, Kohlhase et al. (2002) demonstrated heterozygosity for a cytosine insertion between bases 940 and 941 in the SALL4 gene. The mutation was predicted to result in a truncated protein lacking all 3 double zinc finger motifs.


.0004   DUANE-RADIAL RAY SYNDROME

SALL4, 1-BP DEL, 1904T
SNP: rs1601168967, ClinVar: RCV000003485

In a family in which 8 individuals had Duane-radial ray syndrome (DRRS; 607323), Al-Baradie et al. (2002) identified a heterozygous 1-bp deletion, 1904delT, predicted to result in a frameshift leading to a stop codon after 4 altered amino acids. Six of the affected individuals had bilateral or unilateral Duane syndrome type 1 (see 126800); they showed marked or complete limitation of abduction with minimal or no limitation of adduction. The other 2 affected individuals had Duane syndrome type 3; they showed marked or complete limitation of both abduction and adduction. Seven had bilateral or unilateral thenar hypoplasia. A thumb defect was present in 6. Absent radial pulse, unilateral or bilateral, was noted in 5. Club wrist and short forearm were present in several, as well as shoulder dislocation. Only 1 of the 8 affected members had sensorineural hearing loss.


.0005   DUANE-RADIAL RAY SYNDROME

SALL4, ARG865TER
SNP: rs74315425, ClinVar: RCV000003486, RCV001553330

In affected members of a family with Duane-radial ray syndrome (DRRS; 607323) originally reported by Okihiro et al. (1977), Al-Baradie et al. (2002) found heterozygosity for a 2593C-T change in exon 3 of the SALL4 gene, resulting in an arg-to-ter (R865X) substitution.

Kohlhase et al. (2003) identified the R865X mutation in affected members of family 1 reported by Becker et al. (2002) as having an overlapping phenotype of Okihiro and acrorenoocular syndromes. The proband had bilateral Duane anomaly, bilateral absent thumbs, absent radii, and shortened humeri. She also had slightly dysplastic optic discs and mild bilateral conductive hearing loss. Her affected mother had absent thumbs, shortened forearms, sensorineural hearing loss, and hypoplastic dystopic left kidney.


.0006   DUANE-RADIAL RAY SYNDROME

SALL4, 1-BP DEL, 2425G
SNP: rs1601168015, ClinVar: RCV000003487

In a family in which 3 members had Duane-radial ray syndrome (DRRS; 607323), Al-Baradie et al. (2002) found heterozygosity for a 1-bp deletion, 2425delG, in exon 2 of the SALL4 gene. The deletion was predicted to result in a frameshift leading to a stop codon after 46 altered amino acids. Two of the affected individuals had Duane syndrome type 1 (see 126800), and all 3 had bilateral thumb defects. One had sensorineural hearing loss.


.0007   DUANE-RADIAL RAY SYNDROME

SALL4, 1-BP DEL, 326C
SNP: rs1601171949, ClinVar: RCV000003488

McBride and Read (1994) described a family in which thalidomide embryopathy was diagnosed in the father in childhood based on the nature of the abnormalities: bilateral thumb aplasia and hypoplastic radii in the presence of a history of possible exposure during pregnancy. His daughter was born with bilateral asymmetric radial ray defects consisting of absence of the thumb and first fingers, radial aplasia, and ulnar hypoplasia. Kohlhase et al. (2003) demonstrated a 1-bp deletion in exon 2 of the SALL4 cDNA, 326delC, in the father and daughter. Whereas the initial diagnosis was Holt-Oram syndrome (142900), on reexamination the finding of bilateral Duane anomaly caused revision of the diagnosis to Okihiro syndrome, also known as Duane-radial ray syndrome (607323). This family had been described by McBride and Read (1994) as a possible example of thalidomide mutagenicity.


.0008   DUANE-RADIAL RAY SYNDROME

SALL4, LYS175TER
SNP: rs74315426, ClinVar: RCV000003489

In a patient with sporadic Duane-radial ray syndrome (DRRS; 607323), Kohlhase et al. (2003) identified a heterozygous 523A-T transversion in exon 2 of the SALL4 gene, resulting in a lys175-to-ter (K175X) substitution. The patient had radial abnormalities, persistent foramen ovale, crossed dystopia of the kidneys, and bilateral Duane anomaly. He also had mild epicanthal folds and a broad, flat nasal bridge.


.0009   DUANE-RADIAL RAY SYNDROME

SALL4, ARG617TER
SNP: rs74315427, ClinVar: RCV000003490

In a father and daughter with Duane-radial ray syndrome (DRRS; 607323), Kohlhase et al. (2003) identified a heterozygous 1849C-T transition in exon 2 of the SALL4 gene, resulting in an arg617-to-ter (R617X) substitution. The daughter had bilateral thumb aplasia and radial club hands with shortened arms. She also had ventricular septal defect, hypertelorism with slight epicanthal folds, and flat feet with sandal gaps and broad, short first toes. She had no renal anomalies and no Duane anomaly. The father had less severe limb malformations, flat feet with sandal gaps, and horseshoe kidney. The initial diagnosis was Holt-Oram syndrome (142900), but the finding of Duane anomaly in the father confirmed Duane-radial ray syndrome.


.0010   DUANE-RADIAL RAY SYNDROME

SALL4, DEL
ClinVar: RCV000003491

In affected members of family 2 reported by Becker et al. (2002) as having an overlapping phenotype of Okihiro and acrorenoocular syndromes (DRRS; 607323), Borozdin et al. (2004) identified a heterozygous deletion of at least 135 kb, including the entire SALL4 gene.


.0011   DUANE-RADIAL RAY SYNDROME

SALL4, ARG905TER
SNP: rs74315428, gnomAD: rs74315428, ClinVar: RCV000003492, RCV002464057

In 6 affected members of a family with Duane-radial ray syndrome (DRRS; 607323), Terhal et al. (2006) identified a heterozygous 2713C-T transition in the SALL4 gene, resulting in an arg905-to-ter (R905X) substitution. The truncated protein was predicted to lack the most C-terminal part of the protein including half of the second zinc finger within the most C-terminal double zinc finger domain. The mutant protein probably escapes nonsense-mediated mRNA decay and may retain some residual function. The phenotype in this family was highly variable; only 1 patient had the full syndrome, whereas other family members had only a subset of anomalies.


.0012   DUANE-RADIAL RAY SYNDROME

SALL4, HIS888ARG
SNP: rs74315429, ClinVar: RCV000003493

In an Italian child with a mild form of Duane-radial ray syndrome (DRRS; 607323) who was originally reported by Parentin and Perissutti (2003), Miertus et al. (2006) identified a heterozygous 2663A-G transition in exon 3 of the SALL4 gene, resulting in a his888-to-arg (H888R) substitution in a highly conserved region within the N-terminal ZF motif of the most C-terminal double ZF domain of the protein. The mutation was present in the affected father and maternal grandmother, but not in the unaffected mother or twin sister of the proband. The proband had mild features of Duane-radial ray syndrome as well as cranial midline defects, including facial dysmorphism, pituitary hypoplasia, and a single central incisor. Molecular modeling predicted that the H888R substitution does not result in loss of zinc binding but leads to increased DNA-binding affinity of the domain. Miertus et al. (2006) noted that this was the first reported missense mutation in the SALL4 gene.


.0013   IVIC SYNDROME (1 family)

SALL4, 1-BP DEL, 2607A
SNP: rs1601166963, ClinVar: RCV000003494

In 14 affected members of a large Venezuelan family with IVIC syndrome (IVIC; 147750), originally reported by Arias et al. (1980), Paradisi and Arias (2007) identified a heterozygous 1-bp deletion (2607delA) in exon 3 of the SALL4 gene, resulting in a truncated protein. The mutated mRNA was predicted to escape nonsense-mediated decay because of its location. There was wide intrafamilial phenotypic variability.


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Contributors:
Ada Hamosh - updated : 10/23/2013
Ada Hamosh - updated : 7/1/2013
Cassandra L. Kniffin - updated : 3/26/2007
Cassandra L. Kniffin - updated : 5/16/2006
Cassandra L. Kniffin - updated : 2/9/2006
Victor A. McKusick - updated : 2/7/2006
Cassandra L. Kniffin - updated : 1/3/2006
Victor A. McKusick - updated : 12/27/2005
Cassandra L. Kniffin - updated : 7/6/2005
Victor A. McKusick - updated : 10/12/2004
Victor A. McKusick - updated : 1/9/2004
Patricia A. Hartz - updated : 9/4/2003
Victor A. McKusick - updated : 8/1/2003
Victor A. McKusick - updated : 12/23/2002

Creation Date:
George E. Tiller : 11/13/2002

Edit History:
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tkritzer : 10/20/2004
terry : 10/12/2004
alopez : 1/14/2004
terry : 1/9/2004
mgross : 9/4/2003
carol : 8/1/2003
carol : 1/10/2003
carol : 1/10/2003
tkritzer : 1/8/2003
terry : 12/23/2002
cwells : 11/14/2002
cwells : 11/14/2002