* 600582

ASPARTATE BETA-HYDROXYLASE; ASPH


Alternative titles; symbols

ASPARTYL/ASPARAGINYL-BETA-HYDROXYLASE; HAAH
BAH


Other entities represented in this entry:

JUNCTIN, INCLUDED
JUNCTATE, INCLUDED
HUMBUG, INCLUDED

HGNC Approved Gene Symbol: ASPH

Cytogenetic location: 8q12.3     Genomic coordinates (GRCh38): 8:61,500,556-61,714,592 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
8q12.3 Traboulsi syndrome 601552 AR 3

TEXT

Description

The ASPH gene encodes 3 proteins, aspartate beta-hydroxylase (ASPH), junctin, and junctate (or humbug), which differ significantly in their C-terminal domains. Only ASPH contains a C-terminal catalytic domain, which catalyzes the posttranslational hydroxylation of aspartic acid or asparagine residues within epidermal growth factor (EGF; 131530)-like domains of numerous proteins (Dinchuk et al., 2002).


Cloning and Expression

Korioth et al. (1994) reported the cloning and characterization of the human gene encoding aspartate beta-hydroxylase (ASPH; EC 1.14.11.16). The enzyme recognizes a consensus peptide sequence and specifically hydroxylates the beta carbon of aspartic acid or asparagine residues in certain epidermal growth factor (EGF)-like domains of a number of proteins. Among these are protein C (612283), coagulation factors VII (613878), IX (300746), and X (613872), and the complement factors C1R (613785) and C1S (120580). Korioth et al. (1994) selected a cDNA from an osteosarcoma cDNA library by immunoscreening with an antiserum raised against membrane fractions from these cells. The cDNA was shown to share significant similarity with the bovine sequence. Two transcripts of 4.4 and 2.4 kb were seen with varying intensity in Northern blots of most tissues. Based on Western blots, Korioth et al. (1994) also presented evidence suggesting that posttranslational cleavage of the catalytic carboxyl terminus occurs in the endoplasmic reticulum.

In hepatocellular carcinoma (HCC; 114550), one of the most prevalent tumors in the world which occurs with especially high frequency in sub-Saharan Africa and the Far East, a specific antigen is highly expressed; it is highly expressed also in cholangiocarcinomas. Lavaissiere et al. (1996) reported cDNA cloning of the human gene encoding this antigen, aspartyl(asparaginyl)-beta-hydroxylase (symbolized HAAH by them), and demonstrated that in these tumor lines it is expressed in an enzymatically active form. The gene encodes a deduced 744-amino acid polypeptide with high homology (81%) to the bovine gene (Jia et al., 1992). Lavaissiere et al. (1996) found that their cDNA human sequence was 99% homologous to the sequence for ASPH reported by Korioth et al. (1994), differing only at amino acid residues 565 (tyr to ile), 575 (trp-trp-thr to cys-gly), 585 (asp to gln), and 709 (arg to lys). They noted also a silent TCG-to-TCA transition at peptide residue 161. Lavaissiere et al. (1996) speculated about the possible relationship of the malignant phenotype of regulated aspartyl/asparaginyl-beta-hydroxylation in EGF-like domains of proteins such as the mammalian Notch homologs (e.g., 190198, 600275, and 600276), which are known to be involved in cell differentiation and whose cytoplasmic domains have been shown to be oncogenic.

Junctin is a 26-kD transmembrane calsequestrin (CASQ; 114250)-binding protein detected in junctional sarcoplasmic reticulum (SR) from cardiac and striated muscle tissue. It also colocalizes with the ryanodine receptor (RYR; 180901) and triadin (TRDN; 603283). Using a rabbit junctin cDNA probe to screen a human heart muscle cDNA library, Wetzel et al. (2000) isolated a cDNA encoding junctin. The deduced 225-amino acid protein, which is 86% identical to the canine sequence, contains charged residues adjacent to the 22-amino acid transmembrane domain, suggesting that the N-terminal 24 residues face the cytoplasm with the remainder in the SR lumen. Northern blot analysis detected a 2.8-kb transcript in human cardiac muscle. An increase in junctin expression was detected after birth in rabbit heart muscle.

By screening a heart cDNA library, followed by RT-PCR, Lim et al. (2000) isolated cDNAs encoding the 225-amino acid junctin protein and a 210-amino acid isoform. The authors noted that a 73-residue stretch in junctin has a completely matched region in the ASPH protein. Southern blot analysis indicated that junctin and ASPH exist as a single-copy gene. Northern blot analysis revealed expression of 3.0- and 4.2-kb transcripts in cardiac and skeletal muscle; expression was higher in skeletal muscle. SDS-PAGE analysis of the translated cDNAs showed expression of 26- and 28-kD proteins.

By screening a skeletal muscle cDNA library with a dog junctin probe, Treves et al. (2000) identified cDNAs encoding human junctin and junctate. Sequence analysis predicted that junctate, a 299-amino acid protein, shares the first 93 amino acids of the long isoform of junctin (and, partially, of ASPH), whereas its 64 C-terminal residues are identical to the central region of ASPH. Northern blot analysis detected a 2.6-kb transcript in heart, brain, pancreas, placenta, lung, liver, kidney, and skeletal muscle; highest levels were in heart, brain, and pancreas, and lowest levels were in skeletal muscle. In contrast, junctin was expressed only in cardiac and skeletal muscle. Southern blot and PCR analyses indicated that ASPH, junctin, and junctate are splice variants of the same gene; ASPH uses exons 1, 3, 5, and 8 through 16, whereas junctin uses exons 2, 3, 5, and 6, and junctate uses exons 2 through 5 and 8 through 16. Fluorescence microscopy showed junctate expression in sarco(endo)plasmic reticulum membranes. Immunoblot analysis indicated that junctate is expressed as a 32-kD protein in kidney microsomes. Binding analysis determined that junctate binds calcium with high capacity and moderate affinity.


Gene Structure

Dinchuk et al. (2002) stated that the mouse Asph gene contains 24 exons and spans more than 200 kb.


Mapping

Using FISH, Treves et al. (2000) mapped the ASPH gene to chromosome 8q12.1.


Molecular Genetics

In 3 affected individuals from 3 unrelated families with Traboulsi syndrome (601552), Patel et al. (2014) identified homozygosity for mutations in the ASPH gene: a 5-bp deletion/3-bp insertion (600582.0001) in 1 patient and a missense mutation (R735W; 600582.0002) in the other 2. Both mutations involve only the ASPH isoform and do not affect the junctin or junctate isoforms.

In a boy with Traboulsi syndrome, who was born to consanguineous Peruvian parents, Abarca Barriga et al. (2018) identified homozygosity for a nonsense mutation in the ASPH gene (W57X; 600582.0003). The mutation was identified by whole-exome sequencing. Both parents were heterozygous for the variant, which was not present in the ExAC, gnomAD, 1000 Genomes Project, or Exome Sequencing Project databases or in an in-house Peruvian database of 90 exomes.

In a brother and sister with Traboulsi syndrome from the United Kingdom, Kulkarni et al. (2019) identified compound heterozygous mutations in the ASPH gene: a nonsense mutation (Y565X; 600582.0004) and a splice acceptor site deletion (c.2127-2delA; 600582.0005). The mutations were identified by sequencing of a cataract gene panel. The c.2127-2delA variant was shown to be maternally inherited.


Animal Model

Dinchuk et al. (2002) disrupted the catalytic domain of Asph in mice such that the coding regions of junctin and junctate remained undisturbed. Asph-null mice displayed several developmental defects, including syndactyly, facial dysmorphology, and a mild defect in hard palate formation. The developmental defects were similar to those observed in knockouts and hypomorphs of the Notch (see 190198) ligand Serrate-2 (JAG2; 602570). Dinchuk et al. (2002) proposed that aspartyl beta-hydroxylation of EGF domains can modulate Notch pathway signaling. In addition, crossing Asph-null mice with mice carrying the Apc (611731)-minimum mutation, which leads to the formation of multiple intestinal polyps, resulted in a significant increase in region-specific polyp size and frequency.


ALLELIC VARIANTS ( 5 Selected Examples):

.0001 TRABOULSI SYNDROME

ASPH, 5-BP DEL/3-BP INS, NT1852
  
RCV000125463

In a 19-year-old Saudi woman with Traboulsi syndrome (601552), Patel et al. (2014) identified homozygosity for a 5-bp deletion/3-bp insertion (c.1852_1856delinsGGG) in exon 22 of the ASPH gene, causing a frameshift predicted to result in premature termination (Asn6128GlyfsTer20). However, RT-PCR on blood-derived RNA revealed that the indel results in complete skipping of exon 22 and causes a frameshift (Ser589GlufsTer18) that differs from the predicted frameshift, which the authors suggested might be due to removal of an exon-splicing element. The truncation causes complete loss of the catalytic carboxyl terminal. The mutation, which is specific to the ASPH isoform, was not found in 425 in-house Saudi exomes, 100 Saudi controls by Sanger sequencing, or any publicly available variant databases.


.0002 TRABOULSI SYNDROME

ASPH, ARG735TRP
  
RCV000125464

In 2 unrelated Lebanese patients with Traboulsi syndrome (601552), one of whom was a 16-year-old girl previously reported by Mansour et al. (2013) and the other 1 of 4 Lebanese Druze sisters described by Haddad et al. (2001), Patel et al. (2014) identified homozygosity for a c.2203C-T transition in exon 25 of the ASPH gene, resulting in an arg735-to-trp (R735W) substitution at a completely conserved residue. The mutation, which is specific to the ASPH isoform, was not found in 208 ethnically matched control chromosomes.


.0003 TRABOULSI SYNDROME

ASPH, TRP57TER
  
RCV000761586

In a boy, born of consanguineous Peruvian parents, with Traboulsi syndrome (601552), Abarca Barriga et al. (2018) identified a c.171G-A transition (chr8.62,596,680C-T, ENST00000379454) in exon 2 of the ASPH gene, resulting in a trp57-to-ter (W57X) substitution. The mutation occurred in the cytoplasmic domain and would affect all ASPH isoforms. Both parents were heterozygous for the variant, which was not present in the ExAC, gnomAD, 1000 Genomes project, or Exome Sequencing Project databases or in an in-house Peruvian database of 90 exomes. The mutation was found by whole-exome sequencing, and mutations in over 20 other candidate genes were excluded.


.0004 TRABOULSI SYNDROME

ASPH, TYR565TER
  
RCV001542582

In a brother and sister with Traboulsi syndrome (601552), Kulkarni et al. (2019) identified compound heterozygous mutations in the ASPH gene: a c.1695C-A transversion resulting in a tyr565-to-ter (Y565X) substitution, and c.2127-2delA (600582.0005). The mutations were identified by sequencing of a cataract gene panel. Neither mutation was present in the ExAC and gnomAD databases. The c.2127-2delA variant was shown to be inherited from the mother.


.0005 TRABOULSI SYNDROME

ASPH, IVSAS, DEL, A, -2
  
RCV001542581

For discussion of the c.2127-2delA mutation in the ASPH gene that was found in compound heterozygous state in a brother and sister with Traboulsi syndrome (601552) by Kulkarni et al. (2019), see 600582.0004.


REFERENCES

  1. Abarca Barriga, H. H., Caballero, N., Trubnykova, M., Castro-Mujica, M. D. C., La Serna-Infantes, J. E., Vasquez, F., Hennekam, R. C. A novel ASPH variant extends the phenotype of Shawaf-Traboulsi syndrome. Am. J. Med. Genet. 176A: 2494-2500, 2018. [PubMed: 30194805, related citations] [Full Text]

  2. Dinchuk, J. E., Focht, R. J., Kelley, J. A., Henderson, N. L., Zolotarjova, N. I., Wynn, R., Neff, N. T., Link, J., Huber, R. M., Burn, T. C., Rupar, M. J., Cunningham, M. R., Selling, B. H., Ma, J., Stern, A. A., Hollis, G. F., Stein, R. B., Friedman, P. A. Absence of post-translational aspartyl beta-hydroxylation of epidermal growth factor domains in mice leads to developmental defects and an increased incidence of intestinal neoplasia. J. Biol. Chem. 277: 12970-12977, 2002. [PubMed: 11773073, related citations] [Full Text]

  3. Haddad, R., Uwaydat, S., Dakroub, R., Traboulsi, E. I. Confirmation of the autosomal recessive syndrome of ectopia lentis and distinctive craniofacial appearance. Am. J. Med. Genet. 99: 185-189, 2001. [PubMed: 11241487, related citations] [Full Text]

  4. Jia, S., VanDusen, W. J., Diehl, R. E., Kohl, N. E., Dixon, R. A. F., Elliston, K. O., Stern, A. M., Friedman, P. A. cDNA cloning and expression of bovine aspartyl (asparaginyl) beta-hydroxylase. J. Biol. Chem. 267: 14322-14327, 1992. [PubMed: 1378441, related citations]

  5. Korioth, F., Gieffers, C., Frey, J. Cloning and characterization of the human gene encoding aspartyl beta-hydroxylase. Gene 150: 395-399, 1994. [PubMed: 7821814, related citations] [Full Text]

  6. Kulkarni, N., Lloyd, I. C., Ashworth, J., Biswas, S., Black, G. C. M., NIHR BioResource Consortium, Clayton-Smith, J. Traboulsi syndrome due to ASPH mutation: an under-recognised cause of ectopia lentis. Clin. Dysmorph. 28: 184-189, 2019. [PubMed: 31274573, related citations] [Full Text]

  7. Lavaissiere, L., Jia, S., Nishiyama, M., de la Monte, S., Stern, A. M., Wands, J. R., Friedman, P. A. Overexpression of human aspartyl(asparaginyl)-beta-hydroxylase in hepatocellular carcinoma and cholangiocarcinoma. J. Clin. Invest. 98: 1313-1323, 1996. [PubMed: 8823296, related citations] [Full Text]

  8. Lim, K. Y., Hong, C.-S., Kim, D. H. cDNA cloning and characterization of human cardiac junctin. Gene 255: 35-42, 2000. [PubMed: 10974562, related citations] [Full Text]

  9. Mansour, A. M., Younis, M. H., Dakroub, R. H. Anterior segment imaging and treatment of a case with syndrome of ectopia lentis, spontaneous filtering blebs, and craniofacial dysmorphism. Case Rep. Ophthal. 4: 84-90, 2013. [PubMed: 23687502, images, related citations] [Full Text]

  10. Patel, N., Khan, A. O., Mansour, A., Mohamed, J. Y., Al-Assiri, A., Haddad, R., Jia, X., Xiong, Y., Megarbane, A., Traboulsi, E. I., Alkuraya, F. S. Mutations in ASPH cause facial dysmorphism, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs, or Traboulsi syndrome. Am. J. Hum. Genet. 94: 755-759, 2014. [PubMed: 24768550, images, related citations] [Full Text]

  11. Treves, S., Feriotto, G., Moccagatta, L., Gambari, R., Zorzato, F. Molecular cloning, expression, functional characterization, chromosomal localization, and gene structure of junctate, a novel integral calcium binding protein of sarco(endo)plasmic reticulum membrane. J. Biol. Chem. 275: 39555-39568, 2000. [PubMed: 11007777, related citations] [Full Text]

  12. Wetzel, G. T., Ding, S., Chen, F. Molecular cloning of junctin from human and developing rabbit heart. Molec. Genet. Metab. 69: 252-258, 2000. [PubMed: 10767180, related citations] [Full Text]


Sonja A. Rasmussen - updated : 07/20/2022
Sonja A. Rasmussen - updated : 03/22/2019
Marla J. F. O'Neill - updated : 6/17/2014
Patricia A. Hartz - updated : 3/24/2004
Paul J. Converse - updated : 3/12/2001
Paul J. Converse - updated : 2/19/2001
Creation Date:
Victor A. McKusick : 6/2/1995
carol : 01/26/2024
carol : 07/25/2022
carol : 07/25/2022
carol : 07/21/2022
alopez : 07/20/2022
carol : 03/22/2019
carol : 06/17/2014
mcolton : 6/17/2014
carol : 4/11/2011
carol : 4/8/2011
carol : 3/1/2011
carol : 10/21/2008
carol : 10/9/2008
ckniffin : 2/5/2008
terry : 4/4/2005
mgross : 4/14/2004
terry : 3/24/2004
mgross : 3/13/2001
mgross : 3/12/2001
mgross : 3/12/2001
mgross : 2/19/2001
jamie : 11/22/1996
mark : 11/11/1996
terry : 11/11/1996
mark : 6/9/1995
mark : 6/4/1995
mark : 6/2/1995

* 600582

ASPARTATE BETA-HYDROXYLASE; ASPH


Alternative titles; symbols

ASPARTYL/ASPARAGINYL-BETA-HYDROXYLASE; HAAH
BAH


Other entities represented in this entry:

JUNCTIN, INCLUDED
JUNCTATE, INCLUDED
HUMBUG, INCLUDED

HGNC Approved Gene Symbol: ASPH

SNOMEDCT: 770728003;  


Cytogenetic location: 8q12.3     Genomic coordinates (GRCh38): 8:61,500,556-61,714,592 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
8q12.3 Traboulsi syndrome 601552 Autosomal recessive 3

TEXT

Description

The ASPH gene encodes 3 proteins, aspartate beta-hydroxylase (ASPH), junctin, and junctate (or humbug), which differ significantly in their C-terminal domains. Only ASPH contains a C-terminal catalytic domain, which catalyzes the posttranslational hydroxylation of aspartic acid or asparagine residues within epidermal growth factor (EGF; 131530)-like domains of numerous proteins (Dinchuk et al., 2002).


Cloning and Expression

Korioth et al. (1994) reported the cloning and characterization of the human gene encoding aspartate beta-hydroxylase (ASPH; EC 1.14.11.16). The enzyme recognizes a consensus peptide sequence and specifically hydroxylates the beta carbon of aspartic acid or asparagine residues in certain epidermal growth factor (EGF)-like domains of a number of proteins. Among these are protein C (612283), coagulation factors VII (613878), IX (300746), and X (613872), and the complement factors C1R (613785) and C1S (120580). Korioth et al. (1994) selected a cDNA from an osteosarcoma cDNA library by immunoscreening with an antiserum raised against membrane fractions from these cells. The cDNA was shown to share significant similarity with the bovine sequence. Two transcripts of 4.4 and 2.4 kb were seen with varying intensity in Northern blots of most tissues. Based on Western blots, Korioth et al. (1994) also presented evidence suggesting that posttranslational cleavage of the catalytic carboxyl terminus occurs in the endoplasmic reticulum.

In hepatocellular carcinoma (HCC; 114550), one of the most prevalent tumors in the world which occurs with especially high frequency in sub-Saharan Africa and the Far East, a specific antigen is highly expressed; it is highly expressed also in cholangiocarcinomas. Lavaissiere et al. (1996) reported cDNA cloning of the human gene encoding this antigen, aspartyl(asparaginyl)-beta-hydroxylase (symbolized HAAH by them), and demonstrated that in these tumor lines it is expressed in an enzymatically active form. The gene encodes a deduced 744-amino acid polypeptide with high homology (81%) to the bovine gene (Jia et al., 1992). Lavaissiere et al. (1996) found that their cDNA human sequence was 99% homologous to the sequence for ASPH reported by Korioth et al. (1994), differing only at amino acid residues 565 (tyr to ile), 575 (trp-trp-thr to cys-gly), 585 (asp to gln), and 709 (arg to lys). They noted also a silent TCG-to-TCA transition at peptide residue 161. Lavaissiere et al. (1996) speculated about the possible relationship of the malignant phenotype of regulated aspartyl/asparaginyl-beta-hydroxylation in EGF-like domains of proteins such as the mammalian Notch homologs (e.g., 190198, 600275, and 600276), which are known to be involved in cell differentiation and whose cytoplasmic domains have been shown to be oncogenic.

Junctin is a 26-kD transmembrane calsequestrin (CASQ; 114250)-binding protein detected in junctional sarcoplasmic reticulum (SR) from cardiac and striated muscle tissue. It also colocalizes with the ryanodine receptor (RYR; 180901) and triadin (TRDN; 603283). Using a rabbit junctin cDNA probe to screen a human heart muscle cDNA library, Wetzel et al. (2000) isolated a cDNA encoding junctin. The deduced 225-amino acid protein, which is 86% identical to the canine sequence, contains charged residues adjacent to the 22-amino acid transmembrane domain, suggesting that the N-terminal 24 residues face the cytoplasm with the remainder in the SR lumen. Northern blot analysis detected a 2.8-kb transcript in human cardiac muscle. An increase in junctin expression was detected after birth in rabbit heart muscle.

By screening a heart cDNA library, followed by RT-PCR, Lim et al. (2000) isolated cDNAs encoding the 225-amino acid junctin protein and a 210-amino acid isoform. The authors noted that a 73-residue stretch in junctin has a completely matched region in the ASPH protein. Southern blot analysis indicated that junctin and ASPH exist as a single-copy gene. Northern blot analysis revealed expression of 3.0- and 4.2-kb transcripts in cardiac and skeletal muscle; expression was higher in skeletal muscle. SDS-PAGE analysis of the translated cDNAs showed expression of 26- and 28-kD proteins.

By screening a skeletal muscle cDNA library with a dog junctin probe, Treves et al. (2000) identified cDNAs encoding human junctin and junctate. Sequence analysis predicted that junctate, a 299-amino acid protein, shares the first 93 amino acids of the long isoform of junctin (and, partially, of ASPH), whereas its 64 C-terminal residues are identical to the central region of ASPH. Northern blot analysis detected a 2.6-kb transcript in heart, brain, pancreas, placenta, lung, liver, kidney, and skeletal muscle; highest levels were in heart, brain, and pancreas, and lowest levels were in skeletal muscle. In contrast, junctin was expressed only in cardiac and skeletal muscle. Southern blot and PCR analyses indicated that ASPH, junctin, and junctate are splice variants of the same gene; ASPH uses exons 1, 3, 5, and 8 through 16, whereas junctin uses exons 2, 3, 5, and 6, and junctate uses exons 2 through 5 and 8 through 16. Fluorescence microscopy showed junctate expression in sarco(endo)plasmic reticulum membranes. Immunoblot analysis indicated that junctate is expressed as a 32-kD protein in kidney microsomes. Binding analysis determined that junctate binds calcium with high capacity and moderate affinity.


Gene Structure

Dinchuk et al. (2002) stated that the mouse Asph gene contains 24 exons and spans more than 200 kb.


Mapping

Using FISH, Treves et al. (2000) mapped the ASPH gene to chromosome 8q12.1.


Molecular Genetics

In 3 affected individuals from 3 unrelated families with Traboulsi syndrome (601552), Patel et al. (2014) identified homozygosity for mutations in the ASPH gene: a 5-bp deletion/3-bp insertion (600582.0001) in 1 patient and a missense mutation (R735W; 600582.0002) in the other 2. Both mutations involve only the ASPH isoform and do not affect the junctin or junctate isoforms.

In a boy with Traboulsi syndrome, who was born to consanguineous Peruvian parents, Abarca Barriga et al. (2018) identified homozygosity for a nonsense mutation in the ASPH gene (W57X; 600582.0003). The mutation was identified by whole-exome sequencing. Both parents were heterozygous for the variant, which was not present in the ExAC, gnomAD, 1000 Genomes Project, or Exome Sequencing Project databases or in an in-house Peruvian database of 90 exomes.

In a brother and sister with Traboulsi syndrome from the United Kingdom, Kulkarni et al. (2019) identified compound heterozygous mutations in the ASPH gene: a nonsense mutation (Y565X; 600582.0004) and a splice acceptor site deletion (c.2127-2delA; 600582.0005). The mutations were identified by sequencing of a cataract gene panel. The c.2127-2delA variant was shown to be maternally inherited.


Animal Model

Dinchuk et al. (2002) disrupted the catalytic domain of Asph in mice such that the coding regions of junctin and junctate remained undisturbed. Asph-null mice displayed several developmental defects, including syndactyly, facial dysmorphology, and a mild defect in hard palate formation. The developmental defects were similar to those observed in knockouts and hypomorphs of the Notch (see 190198) ligand Serrate-2 (JAG2; 602570). Dinchuk et al. (2002) proposed that aspartyl beta-hydroxylation of EGF domains can modulate Notch pathway signaling. In addition, crossing Asph-null mice with mice carrying the Apc (611731)-minimum mutation, which leads to the formation of multiple intestinal polyps, resulted in a significant increase in region-specific polyp size and frequency.


ALLELIC VARIANTS 5 Selected Examples):

.0001   TRABOULSI SYNDROME

ASPH, 5-BP DEL/3-BP INS, NT1852
SNP: rs879255574, ClinVar: RCV000125463

In a 19-year-old Saudi woman with Traboulsi syndrome (601552), Patel et al. (2014) identified homozygosity for a 5-bp deletion/3-bp insertion (c.1852_1856delinsGGG) in exon 22 of the ASPH gene, causing a frameshift predicted to result in premature termination (Asn6128GlyfsTer20). However, RT-PCR on blood-derived RNA revealed that the indel results in complete skipping of exon 22 and causes a frameshift (Ser589GlufsTer18) that differs from the predicted frameshift, which the authors suggested might be due to removal of an exon-splicing element. The truncation causes complete loss of the catalytic carboxyl terminal. The mutation, which is specific to the ASPH isoform, was not found in 425 in-house Saudi exomes, 100 Saudi controls by Sanger sequencing, or any publicly available variant databases.


.0002   TRABOULSI SYNDROME

ASPH, ARG735TRP
SNP: rs374385878, gnomAD: rs374385878, ClinVar: RCV000125464

In 2 unrelated Lebanese patients with Traboulsi syndrome (601552), one of whom was a 16-year-old girl previously reported by Mansour et al. (2013) and the other 1 of 4 Lebanese Druze sisters described by Haddad et al. (2001), Patel et al. (2014) identified homozygosity for a c.2203C-T transition in exon 25 of the ASPH gene, resulting in an arg735-to-trp (R735W) substitution at a completely conserved residue. The mutation, which is specific to the ASPH isoform, was not found in 208 ethnically matched control chromosomes.


.0003   TRABOULSI SYNDROME

ASPH, TRP57TER
SNP: rs1563580963, ClinVar: RCV000761586

In a boy, born of consanguineous Peruvian parents, with Traboulsi syndrome (601552), Abarca Barriga et al. (2018) identified a c.171G-A transition (chr8.62,596,680C-T, ENST00000379454) in exon 2 of the ASPH gene, resulting in a trp57-to-ter (W57X) substitution. The mutation occurred in the cytoplasmic domain and would affect all ASPH isoforms. Both parents were heterozygous for the variant, which was not present in the ExAC, gnomAD, 1000 Genomes project, or Exome Sequencing Project databases or in an in-house Peruvian database of 90 exomes. The mutation was found by whole-exome sequencing, and mutations in over 20 other candidate genes were excluded.


.0004   TRABOULSI SYNDROME

ASPH, TYR565TER
SNP: rs781508063, gnomAD: rs781508063, ClinVar: RCV001542582

In a brother and sister with Traboulsi syndrome (601552), Kulkarni et al. (2019) identified compound heterozygous mutations in the ASPH gene: a c.1695C-A transversion resulting in a tyr565-to-ter (Y565X) substitution, and c.2127-2delA (600582.0005). The mutations were identified by sequencing of a cataract gene panel. Neither mutation was present in the ExAC and gnomAD databases. The c.2127-2delA variant was shown to be inherited from the mother.


.0005   TRABOULSI SYNDROME

ASPH, IVSAS, DEL, A, -2
SNP: rs1200332180, gnomAD: rs1200332180, ClinVar: RCV001542581

For discussion of the c.2127-2delA mutation in the ASPH gene that was found in compound heterozygous state in a brother and sister with Traboulsi syndrome (601552) by Kulkarni et al. (2019), see 600582.0004.


REFERENCES

  1. Abarca Barriga, H. H., Caballero, N., Trubnykova, M., Castro-Mujica, M. D. C., La Serna-Infantes, J. E., Vasquez, F., Hennekam, R. C. A novel ASPH variant extends the phenotype of Shawaf-Traboulsi syndrome. Am. J. Med. Genet. 176A: 2494-2500, 2018. [PubMed: 30194805] [Full Text: https://doi.org/10.1002/ajmg.a.40508]

  2. Dinchuk, J. E., Focht, R. J., Kelley, J. A., Henderson, N. L., Zolotarjova, N. I., Wynn, R., Neff, N. T., Link, J., Huber, R. M., Burn, T. C., Rupar, M. J., Cunningham, M. R., Selling, B. H., Ma, J., Stern, A. A., Hollis, G. F., Stein, R. B., Friedman, P. A. Absence of post-translational aspartyl beta-hydroxylation of epidermal growth factor domains in mice leads to developmental defects and an increased incidence of intestinal neoplasia. J. Biol. Chem. 277: 12970-12977, 2002. [PubMed: 11773073] [Full Text: https://doi.org/10.1074/jbc.M110389200]

  3. Haddad, R., Uwaydat, S., Dakroub, R., Traboulsi, E. I. Confirmation of the autosomal recessive syndrome of ectopia lentis and distinctive craniofacial appearance. Am. J. Med. Genet. 99: 185-189, 2001. [PubMed: 11241487] [Full Text: https://doi.org/10.1002/1096-8628(2001)9999:9999<::aid-ajmg1156>3.0.co;2-v]

  4. Jia, S., VanDusen, W. J., Diehl, R. E., Kohl, N. E., Dixon, R. A. F., Elliston, K. O., Stern, A. M., Friedman, P. A. cDNA cloning and expression of bovine aspartyl (asparaginyl) beta-hydroxylase. J. Biol. Chem. 267: 14322-14327, 1992. [PubMed: 1378441]

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Contributors:
Sonja A. Rasmussen - updated : 07/20/2022
Sonja A. Rasmussen - updated : 03/22/2019
Marla J. F. O'Neill - updated : 6/17/2014
Patricia A. Hartz - updated : 3/24/2004
Paul J. Converse - updated : 3/12/2001
Paul J. Converse - updated : 2/19/2001

Creation Date:
Victor A. McKusick : 6/2/1995

Edit History:
carol : 01/26/2024
carol : 07/25/2022
carol : 07/25/2022
carol : 07/21/2022
alopez : 07/20/2022
carol : 03/22/2019
carol : 06/17/2014
mcolton : 6/17/2014
carol : 4/11/2011
carol : 4/8/2011
carol : 3/1/2011
carol : 10/21/2008
carol : 10/9/2008
ckniffin : 2/5/2008
terry : 4/4/2005
mgross : 4/14/2004
terry : 3/24/2004
mgross : 3/13/2001
mgross : 3/12/2001
mgross : 3/12/2001
mgross : 2/19/2001
jamie : 11/22/1996
mark : 11/11/1996
terry : 11/11/1996
mark : 6/9/1995
mark : 6/4/1995
mark : 6/2/1995