* 611654

CENTROSOME SPINDLE POLE-ASSOCIATED PROTEIN 1; CSPP1


Alternative titles; symbols

CSPP


Other entities represented in this entry:

CSPP1-S, INCLUDED
CSPP1-L, INCLUDED

HGNC Approved Gene Symbol: CSPP1

Cytogenetic location: 8q13.1-q13.2     Genomic coordinates (GRCh38): 8:67,064,368-67,196,614 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
8q13.1-q13.2 Joubert syndrome 21 615636 AR 3

TEXT

Description

CSPP1 interacts with centrosomes and microtubules and plays a role in cell-cycle progression and spindle organization (Patzke et al., 2005; Patzke et al., 2006).


Cloning and Expression

By cDNA representational difference analysis to search for genes associated with high-grade human non-Hodgkin B-cell lymphoma, followed by screening a human testis cDNA library, Patzke et al. (2005) cloned a partial CSPP1 cDNA, herein termed CSPP1-S. The deduced 876-amino acid protein is highly charged and has a calculated molecular mass of 101.5 kD. CSPP1 has an N-terminal bipartite nuclear localization signal, a proline-rich region, a central domain consisting of 3 coiled-coil regions, and a C-terminal domain. Immunofluorescence studies localized CSPP1-S along microtubules, accumulating mainly around the centrosome in transfected interphase HEK293T cells. Northern blot analysis of human tissues detected a 4.4-kb transcript in testis.

By database analysis, Patzke et al. (2006) identified a CSPP1 isoform, which they called CSPP1-L, of 1,221 amino acids and a calculated molecular mass of 142 kD. CSPP1-L contains an N-terminal addition of 294 amino acids and a 51-amino acid insertion in the coiled-coil domain. RT-PCR detected CSPP1-L expression at higher levels than CSPP1-S in human testis and in asynchronously growing HEK293T cells and Reh cells. Relative expression levels of CSPP1-S and CSPP1-L behaved inversely in asynchronously growing Reh cells; CSPP1-S expression decreased from G1 to S and G2/M phase, whereas CSPP1-L levels increased throughout the cell cycle. Immunofluorescence studies localized CSPP1-L to the microtubules and centrosomes, accumulating at the microtubule organization center in interphase, similar to CSPP1-S. By nocodazole exposure, Patzke et al. (2006) showed that both CSPP1-S and CSPP1-L localized to centrosomes independently of microtubules.

Akizu et al. (2014) found high expression of the CSPP1 gene in human adult and fetal brain tissue, with enrichment in the cerebellum.


Gene Function

Patzke et al. (2005) showed that overexpression of CSPP1-S in HEK293T cells blocked cell-cycle progression in G1 phase and perturbed spindle formation and chromosome congression in mitosis, displaying multiple spindle poles and condensed chromosomes aligned in ring-like structures around the spindle poles. RNAi depletion of CSPP1-S perturbed cell-cycle progression in late S phase under activation of the DNA replication checkpoint.

Patzke et al. (2006) showed that overexpression of both CSPP1-S and CSPP1-L impaired mitotic progression; however, different phenotypes were associated with each isoform. Cells overexpressing CSPP1-L displayed frequent bipolar spindles with lagging chromosomes as well as formation of monopolar spindles. However, overexpression of CSPP1-S caused multipolar spindles and seldom showed metaphase alignment. Using CSPP1-S and CSPP1-L mutant constructs, they showed that the 294-amino acid N-terminal extension was associated with increased multipolar spindles, decreased numbers of monopolar spindles, and bipolar spindles with lagging chromosomes. Both CSPP1-S and CSPP1-L-expressing cells impaired cell-cycle progression in the G1 phase but to different degrees. C-terminal truncated mutants containing a domain common to both CSPP1-S and CSPP1-L localized to the centrosomes throughout the cell cycle.


Gene Structure

Patzke et al. (2006) determined that the CSPP1 gene contains 30 exons. The CSPP1-S isoform results from alternative splicing of exon 4 and lacks exon 17. The CSPP1-L isoform contains 29 exons and lacks exon 4.


Mapping

By genomic sequence analysis, Patzke et al. (2005) mapped the CSPP1 gene to chromosome 8q13.2.


Molecular Genetics

In 19 patients from 15 families with Joubert syndrome-21 (JBTS21; 615636), Tuz et al. (2014) identified biallelic truncating mutations in the CSPP1 gene (see, e.g., 611654.0001-611654.0007). When samples were available, Sanger sequencing confirmed that the variants segregated in the families. There was wide phenotypic variation, but all patients had cerebellar vermis hypoplasia, causing the 'molar tooth sign' on brain MRI, hypotonia, delayed development, eye movement abnormalities, and abnormal breathing. Some patients had features of Jeune asphyxiating thoracic dystrophy (see SRTD1, 208500). There were no apparent genotype/phenotype correlations. Fibroblasts from 2 unrelated patients showed absence of CSPP1 immunostaining in the axoneme, although the signal at the base of the cilium remained. Patient cells showed defects in ciliogenesis, with decreased numbers of cilia, decreased ciliary length, and evidence of decreased trafficking of the ciliary proteins ARL13B (608922) and ADCY3 (600291) to the axoneme compared to controls. Collectively, the results suggested a loss of function.

In 3 patients from 2 consanguineous Canadian Hutterite families with JBTS21, Shaheen et al. (2014) identified a homozygous truncating mutation in the CSPP1 gene (611654.0008). Two fetuses from a consanguineous Saudi family with a more severe phenotype reminiscent of Meckel syndrome (249000) were found to carry a different homozygous truncating mutation (611654.0009). A patient skin sample showed decreased numbers of ciliated fibroblasts, with complete loss of the ciliary localization of RPGRIP1L (610937) compared to controls. These cells also showed markedly impaired SHH (600725) signaling, indicating that the ciliogenesis defect has downstream consequences. Analysis of the cell cycle showed no difference between patient cells and control cells.

In 6 unrelated patients with Joubert syndrome, Akizu et al. (2014) identified biallelic truncating or splice site mutations in the CSPP1 gene (see, e.g., 611654.0010-611654.0011). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. The patients were ascertained from a larger cohort of 287 probands with Joubert syndrome who underwent whole-exome sequencing. The patients had a classic phenotype, with psychomotor delay, hypotonia, ataxia, breathing difficulties, variable ophthalmologic findings, and the molar tooth sign on brain imaging. Hepatic fibrosis, renal abnormalities, and polydactyly were not present. Fibroblasts from 1 patient showed absence of the CSPP1 protein, but normal cell proliferation. Serum-starved patient cells showed defective ciliogenesis, with decreased levels of ARL13B, although the number of centrosomes was normal. Akizu et al. (2014) concluded that CSPP1 is involved in neural-specific functions of primary cilia.


Animal Model

Tuz et al. (2014) found ubiquitous expression of the cspp1a gene in zebrafish at 24 hours postfertilization, including in the brain and ear. At 48 hours, expression decreased globally, but remained high in the cerebellar fold, ear, and nose pits. Morpholino knockdown of the cspp1a gene in zebrafish embryos resulted in a curved body shape, dilated ventricles, and pronephric cysts, consistent with a ciliopathy. The neurocranium also showed patterning defects. The presence of cilia did not appear to be altered in zebrafish mutants, but there was reduced ciliary localization of arl13b.


ALLELIC VARIANTS ( 11 Selected Examples):

.0001 JOUBERT SYNDROME 21

CSPP1, ARG774TER
  
RCV000087066

In a 1-year-old African American patient with Joubert syndrome-21 (JBTS21; 615636), Tuz et al. (2014) identified a homozygous c.2320C-T transition in the CSPP1 gene, resulting in an arg774-to-ter (R774X) substitution. The mutation was found by Sanger sequencing of a candidate region on chromosome 8q13.1-q21.12 identified by SNP microarray analysis. It was not present in the Exome Variant Server database. The patient had a severe phenotype, with encephalocele, optic atrophy, short ribs, bell-shaped chest, and pulmonary hypoplasia.


.0002 JOUBERT SYNDROME 21

CSPP1, 2-BP DEL, 2244AA
  
RCV000087067...

In 2 sibs of mixed European descent with JBTS21 (615636), Tuz et al. (2014) identified compound heterozygous mutations in the CSPP1 gene: a 2-bp deletion (c.2244_2245delAA), resulting in a frameshift and premature termination (Glu750GlyfsTer30), and a 1-bp deletion (c.2280delA; 611654.0003), resulting in a frameshift and premature termination (Glu761LysfsTer35). The patients had a severe phenotype, with feeding abnormalities, nystagmus, short ribs, bell-shaped chest, and pulmonary hypoplasia.


.0003 JOUBERT SYNDROME 21

CSPP1, 1-BP DEL, 2280A
  
RCV000087068

For discussion of the 1-bp deletion in the CSPP1 gene (c.2280delA) that was found in compound heterozygous state in 2 sibs with Joubert syndrome-21 (JBTS21; 615636) by Tuz et al. (2014), see 611654.0002.


.0004 JOUBERT SYNDROME 21

CSPP1, 1-BP INS, 3211A
  
RCV000087069

In 3 unrelated Brazilian patients with Joubert syndrome-21 (JBTS21; 615636), Tuz et al. (2014) identified compound heterozygous mutations in the CSPP1 gene: a 1-bp insertion (c.3211_3212insA), resulting in a frameshift and premature termination (Tyr1071Ter), and a G-to-A transition in intron 22 (c.2953+1G-A; 611654.0005), resulting in a splice site mutation.


.0005 JOUBERT SYNDROME 21

CSPP1, IVS22DS, G-A, +1
  
RCV000087070

For discussion of the splice site mutation in the CSPP1 gene (c.2953+1G-A) that was found in compound heterozygous state in patients with Joubert syndrome-21 (JBTS21; 615636) by Tuz et al. (2014), see 611654.0004.


.0006 JOUBERT SYNDROME 21

CSPP1, 2-BP DEL, 2527AT
  
RCV000087071

In 2 unrelated patients of Turkish and Lebanese descent, respectively, with Joubert syndrome-21 (JBTS21; 615636), Tuz et al. (2014) identified a homozygous 2-bp deletion (c.2527_2528delAT), resulting in a frameshift and premature termination (Met843GlufsTer25). Two Turkish sibs from a third family with the disorder were compound heterozygous for c.2527_2528delAT and a c.658C-T transition, resulting in an arg220-to-ter (R220X; 611654.0007) substitution.


.0007 JOUBERT SYNDROME 21

CSPP1, ARG220TER
  
RCV000087072

For discussion of the arg220-to-ter (R220X) mutation in the CSPP1 gene that was found in compound heterozygous state in patients with Joubert syndrome-21 (JBTS21; 615636) by Tuz et al. (2014), see 611654.0006.


.0008 JOUBERT SYNDROME 21

CSPP1, 2-BP DEL, 363TA
  
RCV000087073

In a girl, born of related Schmiedeleut Hutterite Canadian parents, with Joubert syndrome-21 (JBTS21; 615636), Shaheen et al. (2014) identified a homozygous 2-bp deletion (c.363_364delTA) in the CSPP1 gene, resulting in a frameshift and premature termination (His121GlnfsTer22). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was absent from publicly available databases. Two sibs from another Schmiedeleut Hutterite family were also found to carry this homozygous mutation. These patients had a more severe form of the disorder with multiple malformations of the posterior fossa and cerebellum; both died in infancy.


.0009 JOUBERT SYNDROME 21

CSPP1, 4-BP DEL, 2244AAGA
  
RCV000087074...

In a stillborn fetus, born of consanguineous Saudi parents, with Joubert syndrome-21 (JBTS21; 615636), Shaheen et al. (2014) identified a homozygous 4-bp deletion (c.2244_2247delAAGA) in the CSPP1 gene, resulting in a frameshift and premature termination (Glu750LysfsTer7). The mutation segregated with the disorder in the family. This fetus and another stillborn fetus in this family had severe multisystem defects, including hydranencephaly, occipital encephalocele, wide cranial sutures, anophthalmia, single nostril, and hyperechogenic kidneys. The phenotype was reminiscent of Meckel syndrome (MKS; 249000). A third pregnancy ended in spontaneous first-trimester abortion. A patient skin sample showed decreased numbers of ciliated fibroblasts, with complete loss of the ciliary localization of RPGRIP1L (610937) compared to controls. These cells also showed markedly impaired SHH (600725) signaling, indicating that the ciliogenesis defect has downstream consequences. Analysis of the cell cycle showed no difference between patient cells and control cells. Shaheen et al. (2014) noted that this mutation affects both CSPP1 isoforms, which may have contributed to the severe phenotype. CSPP1 mutations were not identified in 89 additional patients with MKS.


.0010 JOUBERT SYNDROME 21

CSPP1, GLN218TER
  
RCV000087075

In a Mexican boy with Joubert syndrome-21 (JBTS21; 615636), Akizu et al. (2014) identified a homozygous c.652C-T transition in the CSPP1 gene, resulting in a gln218-to-ter (Q218X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the Exome Variant Server database or in control exomes from 2,500 individuals. The patient had psychomotor delay, hypotonia, ataxia, retinopathy, oculomotor apraxia, nystagmus, mild sensorineural hearing loss, obesity, the molar tooth sign on brain imaging, and thin corpus callosum.


.0011 JOUBERT SYNDROME 21

CSPP1, ARG925TER
  
RCV000087076

In a Libyan boy, born of consanguineous parents, with Joubert syndrome-21 (JBTS21; 615636), Akizu et al. (2014) identified a homozygous c.2773C-T transition in the CSPP1 gene, resulting in an arg925-to-ter (R925X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the Exome Variant Server database or in control exomes from 2,500 individuals. The patient had psychomotor delay, hypotonia, breathing abnormalities, nystagmus, the molar tooth sign on brain imaging, and thin corpus callosum.


REFERENCES

  1. Akizu, N., Silhavy, J. L., Rosti, R. O., Scott, E., Fenstermaker, A. G., Schroth, J., Zaki, M. S., Sanchez, H., Gupta, N., Kabra, M., Kara, M., Ben-Omran, T., and 12 others. Mutations in CSPP1 lead to classical Joubert syndrome. Am. J. Hum. Genet. 94: 80-86, 2014. [PubMed: 24360807, images, related citations] [Full Text]

  2. Patzke, S., Hauge, H., Sioud, M., Finne, E. F., Sivertsen, E. A., Delabie, J., Stokke, T., Aasheim, H.-C. Identification of a novel centrosome/microtubule-associated coiled-coil protein involved in cell-cycle progression and spindle organization. Oncogene 24: 1159-1173, 2005. [PubMed: 15580290, related citations] [Full Text]

  3. Patzke, S., Stokke, T., Aasheim, H.-C. CSPP and CSPP-L associate with centrosomes and microtubules and differently affect microtubule organization. J. Cell. Physiol. 209: 199-210, 2006. [PubMed: 16826565, related citations] [Full Text]

  4. Shaheen, R., Shamseldin, H. E., Loucks, C. M., Seidahmed, M. Z., Ansari, S., Ibrahim Khalil, M., Al-Yacoub, N., Davis, E. E., Mola, N. A., Szymanska, J., Herridge, W., Chudley, A. E., and 10 others. Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans. Am. J. Hum. Genet. 94: 73-79, 2014. [PubMed: 24360803, images, related citations] [Full Text]

  5. Tuz, K., Bachmann-Gagescu, R., O'Day, D. R., Hua, K., Isabella, C. R., Phelps, I. G., Stolarski, A. E., O'Roak, B. J., Dempsey, J. C., Lourenco, C., Alswaid, A., Bonnemann, C. G., and 15 others. Mutations in CSPP1 cause primary cilia abnormalities and Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. Am. J. Hum. Genet. 94: 62-72, 2014. Note: Erratum: Am. J. Hum. Genet. 94: 310 only, 2014. [PubMed: 24360808, images, related citations] [Full Text]


Contributors:
Cassandra L. Kniffin - updated : 2/11/2014
Creation Date:
Dorothy S. Reilly : 12/10/2007
alopez : 08/11/2015
mcolton : 7/31/2015
alopez : 2/9/2015
alopez : 2/25/2014
carol : 2/17/2014
mcolton : 2/12/2014
ckniffin : 2/11/2014
carol : 12/11/2007
wwang : 12/10/2007

* 611654

CENTROSOME SPINDLE POLE-ASSOCIATED PROTEIN 1; CSPP1


Alternative titles; symbols

CSPP


Other entities represented in this entry:

CSPP1-S, INCLUDED
CSPP1-L, INCLUDED

HGNC Approved Gene Symbol: CSPP1

Cytogenetic location: 8q13.1-q13.2     Genomic coordinates (GRCh38): 8:67,064,368-67,196,614 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
8q13.1-q13.2 Joubert syndrome 21 615636 Autosomal recessive 3

TEXT

Description

CSPP1 interacts with centrosomes and microtubules and plays a role in cell-cycle progression and spindle organization (Patzke et al., 2005; Patzke et al., 2006).


Cloning and Expression

By cDNA representational difference analysis to search for genes associated with high-grade human non-Hodgkin B-cell lymphoma, followed by screening a human testis cDNA library, Patzke et al. (2005) cloned a partial CSPP1 cDNA, herein termed CSPP1-S. The deduced 876-amino acid protein is highly charged and has a calculated molecular mass of 101.5 kD. CSPP1 has an N-terminal bipartite nuclear localization signal, a proline-rich region, a central domain consisting of 3 coiled-coil regions, and a C-terminal domain. Immunofluorescence studies localized CSPP1-S along microtubules, accumulating mainly around the centrosome in transfected interphase HEK293T cells. Northern blot analysis of human tissues detected a 4.4-kb transcript in testis.

By database analysis, Patzke et al. (2006) identified a CSPP1 isoform, which they called CSPP1-L, of 1,221 amino acids and a calculated molecular mass of 142 kD. CSPP1-L contains an N-terminal addition of 294 amino acids and a 51-amino acid insertion in the coiled-coil domain. RT-PCR detected CSPP1-L expression at higher levels than CSPP1-S in human testis and in asynchronously growing HEK293T cells and Reh cells. Relative expression levels of CSPP1-S and CSPP1-L behaved inversely in asynchronously growing Reh cells; CSPP1-S expression decreased from G1 to S and G2/M phase, whereas CSPP1-L levels increased throughout the cell cycle. Immunofluorescence studies localized CSPP1-L to the microtubules and centrosomes, accumulating at the microtubule organization center in interphase, similar to CSPP1-S. By nocodazole exposure, Patzke et al. (2006) showed that both CSPP1-S and CSPP1-L localized to centrosomes independently of microtubules.

Akizu et al. (2014) found high expression of the CSPP1 gene in human adult and fetal brain tissue, with enrichment in the cerebellum.


Gene Function

Patzke et al. (2005) showed that overexpression of CSPP1-S in HEK293T cells blocked cell-cycle progression in G1 phase and perturbed spindle formation and chromosome congression in mitosis, displaying multiple spindle poles and condensed chromosomes aligned in ring-like structures around the spindle poles. RNAi depletion of CSPP1-S perturbed cell-cycle progression in late S phase under activation of the DNA replication checkpoint.

Patzke et al. (2006) showed that overexpression of both CSPP1-S and CSPP1-L impaired mitotic progression; however, different phenotypes were associated with each isoform. Cells overexpressing CSPP1-L displayed frequent bipolar spindles with lagging chromosomes as well as formation of monopolar spindles. However, overexpression of CSPP1-S caused multipolar spindles and seldom showed metaphase alignment. Using CSPP1-S and CSPP1-L mutant constructs, they showed that the 294-amino acid N-terminal extension was associated with increased multipolar spindles, decreased numbers of monopolar spindles, and bipolar spindles with lagging chromosomes. Both CSPP1-S and CSPP1-L-expressing cells impaired cell-cycle progression in the G1 phase but to different degrees. C-terminal truncated mutants containing a domain common to both CSPP1-S and CSPP1-L localized to the centrosomes throughout the cell cycle.


Gene Structure

Patzke et al. (2006) determined that the CSPP1 gene contains 30 exons. The CSPP1-S isoform results from alternative splicing of exon 4 and lacks exon 17. The CSPP1-L isoform contains 29 exons and lacks exon 4.


Mapping

By genomic sequence analysis, Patzke et al. (2005) mapped the CSPP1 gene to chromosome 8q13.2.


Molecular Genetics

In 19 patients from 15 families with Joubert syndrome-21 (JBTS21; 615636), Tuz et al. (2014) identified biallelic truncating mutations in the CSPP1 gene (see, e.g., 611654.0001-611654.0007). When samples were available, Sanger sequencing confirmed that the variants segregated in the families. There was wide phenotypic variation, but all patients had cerebellar vermis hypoplasia, causing the 'molar tooth sign' on brain MRI, hypotonia, delayed development, eye movement abnormalities, and abnormal breathing. Some patients had features of Jeune asphyxiating thoracic dystrophy (see SRTD1, 208500). There were no apparent genotype/phenotype correlations. Fibroblasts from 2 unrelated patients showed absence of CSPP1 immunostaining in the axoneme, although the signal at the base of the cilium remained. Patient cells showed defects in ciliogenesis, with decreased numbers of cilia, decreased ciliary length, and evidence of decreased trafficking of the ciliary proteins ARL13B (608922) and ADCY3 (600291) to the axoneme compared to controls. Collectively, the results suggested a loss of function.

In 3 patients from 2 consanguineous Canadian Hutterite families with JBTS21, Shaheen et al. (2014) identified a homozygous truncating mutation in the CSPP1 gene (611654.0008). Two fetuses from a consanguineous Saudi family with a more severe phenotype reminiscent of Meckel syndrome (249000) were found to carry a different homozygous truncating mutation (611654.0009). A patient skin sample showed decreased numbers of ciliated fibroblasts, with complete loss of the ciliary localization of RPGRIP1L (610937) compared to controls. These cells also showed markedly impaired SHH (600725) signaling, indicating that the ciliogenesis defect has downstream consequences. Analysis of the cell cycle showed no difference between patient cells and control cells.

In 6 unrelated patients with Joubert syndrome, Akizu et al. (2014) identified biallelic truncating or splice site mutations in the CSPP1 gene (see, e.g., 611654.0010-611654.0011). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. The patients were ascertained from a larger cohort of 287 probands with Joubert syndrome who underwent whole-exome sequencing. The patients had a classic phenotype, with psychomotor delay, hypotonia, ataxia, breathing difficulties, variable ophthalmologic findings, and the molar tooth sign on brain imaging. Hepatic fibrosis, renal abnormalities, and polydactyly were not present. Fibroblasts from 1 patient showed absence of the CSPP1 protein, but normal cell proliferation. Serum-starved patient cells showed defective ciliogenesis, with decreased levels of ARL13B, although the number of centrosomes was normal. Akizu et al. (2014) concluded that CSPP1 is involved in neural-specific functions of primary cilia.


Animal Model

Tuz et al. (2014) found ubiquitous expression of the cspp1a gene in zebrafish at 24 hours postfertilization, including in the brain and ear. At 48 hours, expression decreased globally, but remained high in the cerebellar fold, ear, and nose pits. Morpholino knockdown of the cspp1a gene in zebrafish embryos resulted in a curved body shape, dilated ventricles, and pronephric cysts, consistent with a ciliopathy. The neurocranium also showed patterning defects. The presence of cilia did not appear to be altered in zebrafish mutants, but there was reduced ciliary localization of arl13b.


ALLELIC VARIANTS 11 Selected Examples):

.0001   JOUBERT SYNDROME 21

CSPP1, ARG774TER
SNP: rs587777138, gnomAD: rs587777138, ClinVar: RCV000087066

In a 1-year-old African American patient with Joubert syndrome-21 (JBTS21; 615636), Tuz et al. (2014) identified a homozygous c.2320C-T transition in the CSPP1 gene, resulting in an arg774-to-ter (R774X) substitution. The mutation was found by Sanger sequencing of a candidate region on chromosome 8q13.1-q21.12 identified by SNP microarray analysis. It was not present in the Exome Variant Server database. The patient had a severe phenotype, with encephalocele, optic atrophy, short ribs, bell-shaped chest, and pulmonary hypoplasia.


.0002   JOUBERT SYNDROME 21

CSPP1, 2-BP DEL, 2244AA
SNP: rs587777139, ClinVar: RCV000087067, RCV001555416

In 2 sibs of mixed European descent with JBTS21 (615636), Tuz et al. (2014) identified compound heterozygous mutations in the CSPP1 gene: a 2-bp deletion (c.2244_2245delAA), resulting in a frameshift and premature termination (Glu750GlyfsTer30), and a 1-bp deletion (c.2280delA; 611654.0003), resulting in a frameshift and premature termination (Glu761LysfsTer35). The patients had a severe phenotype, with feeding abnormalities, nystagmus, short ribs, bell-shaped chest, and pulmonary hypoplasia.


.0003   JOUBERT SYNDROME 21

CSPP1, 1-BP DEL, 2280A
SNP: rs587777140, ClinVar: RCV000087068

For discussion of the 1-bp deletion in the CSPP1 gene (c.2280delA) that was found in compound heterozygous state in 2 sibs with Joubert syndrome-21 (JBTS21; 615636) by Tuz et al. (2014), see 611654.0002.


.0004   JOUBERT SYNDROME 21

CSPP1, 1-BP INS, 3211A
SNP: rs587777141, ClinVar: RCV000087069

In 3 unrelated Brazilian patients with Joubert syndrome-21 (JBTS21; 615636), Tuz et al. (2014) identified compound heterozygous mutations in the CSPP1 gene: a 1-bp insertion (c.3211_3212insA), resulting in a frameshift and premature termination (Tyr1071Ter), and a G-to-A transition in intron 22 (c.2953+1G-A; 611654.0005), resulting in a splice site mutation.


.0005   JOUBERT SYNDROME 21

CSPP1, IVS22DS, G-A, +1
SNP: rs587777142, gnomAD: rs587777142, ClinVar: RCV000087070

For discussion of the splice site mutation in the CSPP1 gene (c.2953+1G-A) that was found in compound heterozygous state in patients with Joubert syndrome-21 (JBTS21; 615636) by Tuz et al. (2014), see 611654.0004.


.0006   JOUBERT SYNDROME 21

CSPP1, 2-BP DEL, 2527AT
SNP: rs587777143, gnomAD: rs587777143, ClinVar: RCV000087071

In 2 unrelated patients of Turkish and Lebanese descent, respectively, with Joubert syndrome-21 (JBTS21; 615636), Tuz et al. (2014) identified a homozygous 2-bp deletion (c.2527_2528delAT), resulting in a frameshift and premature termination (Met843GlufsTer25). Two Turkish sibs from a third family with the disorder were compound heterozygous for c.2527_2528delAT and a c.658C-T transition, resulting in an arg220-to-ter (R220X; 611654.0007) substitution.


.0007   JOUBERT SYNDROME 21

CSPP1, ARG220TER
SNP: rs375113643, gnomAD: rs375113643, ClinVar: RCV000087072

For discussion of the arg220-to-ter (R220X) mutation in the CSPP1 gene that was found in compound heterozygous state in patients with Joubert syndrome-21 (JBTS21; 615636) by Tuz et al. (2014), see 611654.0006.


.0008   JOUBERT SYNDROME 21

CSPP1, 2-BP DEL, 363TA
SNP: rs1554562278, ClinVar: RCV000087073

In a girl, born of related Schmiedeleut Hutterite Canadian parents, with Joubert syndrome-21 (JBTS21; 615636), Shaheen et al. (2014) identified a homozygous 2-bp deletion (c.363_364delTA) in the CSPP1 gene, resulting in a frameshift and premature termination (His121GlnfsTer22). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was absent from publicly available databases. Two sibs from another Schmiedeleut Hutterite family were also found to carry this homozygous mutation. These patients had a more severe form of the disorder with multiple malformations of the posterior fossa and cerebellum; both died in infancy.


.0009   JOUBERT SYNDROME 21

CSPP1, 4-BP DEL, 2244AAGA
SNP: rs587777145, ClinVar: RCV000087074, RCV000162164, RCV001008753

In a stillborn fetus, born of consanguineous Saudi parents, with Joubert syndrome-21 (JBTS21; 615636), Shaheen et al. (2014) identified a homozygous 4-bp deletion (c.2244_2247delAAGA) in the CSPP1 gene, resulting in a frameshift and premature termination (Glu750LysfsTer7). The mutation segregated with the disorder in the family. This fetus and another stillborn fetus in this family had severe multisystem defects, including hydranencephaly, occipital encephalocele, wide cranial sutures, anophthalmia, single nostril, and hyperechogenic kidneys. The phenotype was reminiscent of Meckel syndrome (MKS; 249000). A third pregnancy ended in spontaneous first-trimester abortion. A patient skin sample showed decreased numbers of ciliated fibroblasts, with complete loss of the ciliary localization of RPGRIP1L (610937) compared to controls. These cells also showed markedly impaired SHH (600725) signaling, indicating that the ciliogenesis defect has downstream consequences. Analysis of the cell cycle showed no difference between patient cells and control cells. Shaheen et al. (2014) noted that this mutation affects both CSPP1 isoforms, which may have contributed to the severe phenotype. CSPP1 mutations were not identified in 89 additional patients with MKS.


.0010   JOUBERT SYNDROME 21

CSPP1, GLN218TER
SNP: rs587777146, ClinVar: RCV000087075

In a Mexican boy with Joubert syndrome-21 (JBTS21; 615636), Akizu et al. (2014) identified a homozygous c.652C-T transition in the CSPP1 gene, resulting in a gln218-to-ter (Q218X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the Exome Variant Server database or in control exomes from 2,500 individuals. The patient had psychomotor delay, hypotonia, ataxia, retinopathy, oculomotor apraxia, nystagmus, mild sensorineural hearing loss, obesity, the molar tooth sign on brain imaging, and thin corpus callosum.


.0011   JOUBERT SYNDROME 21

CSPP1, ARG925TER
SNP: rs537456518, gnomAD: rs537456518, ClinVar: RCV000087076

In a Libyan boy, born of consanguineous parents, with Joubert syndrome-21 (JBTS21; 615636), Akizu et al. (2014) identified a homozygous c.2773C-T transition in the CSPP1 gene, resulting in an arg925-to-ter (R925X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the Exome Variant Server database or in control exomes from 2,500 individuals. The patient had psychomotor delay, hypotonia, breathing abnormalities, nystagmus, the molar tooth sign on brain imaging, and thin corpus callosum.


REFERENCES

  1. Akizu, N., Silhavy, J. L., Rosti, R. O., Scott, E., Fenstermaker, A. G., Schroth, J., Zaki, M. S., Sanchez, H., Gupta, N., Kabra, M., Kara, M., Ben-Omran, T., and 12 others. Mutations in CSPP1 lead to classical Joubert syndrome. Am. J. Hum. Genet. 94: 80-86, 2014. [PubMed: 24360807] [Full Text: https://doi.org/10.1016/j.ajhg.2013.11.015]

  2. Patzke, S., Hauge, H., Sioud, M., Finne, E. F., Sivertsen, E. A., Delabie, J., Stokke, T., Aasheim, H.-C. Identification of a novel centrosome/microtubule-associated coiled-coil protein involved in cell-cycle progression and spindle organization. Oncogene 24: 1159-1173, 2005. [PubMed: 15580290] [Full Text: https://doi.org/10.1038/sj.onc.1208267]

  3. Patzke, S., Stokke, T., Aasheim, H.-C. CSPP and CSPP-L associate with centrosomes and microtubules and differently affect microtubule organization. J. Cell. Physiol. 209: 199-210, 2006. [PubMed: 16826565] [Full Text: https://doi.org/10.1002/jcp.20725]

  4. Shaheen, R., Shamseldin, H. E., Loucks, C. M., Seidahmed, M. Z., Ansari, S., Ibrahim Khalil, M., Al-Yacoub, N., Davis, E. E., Mola, N. A., Szymanska, J., Herridge, W., Chudley, A. E., and 10 others. Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans. Am. J. Hum. Genet. 94: 73-79, 2014. [PubMed: 24360803] [Full Text: https://doi.org/10.1016/j.ajhg.2013.11.010]

  5. Tuz, K., Bachmann-Gagescu, R., O'Day, D. R., Hua, K., Isabella, C. R., Phelps, I. G., Stolarski, A. E., O'Roak, B. J., Dempsey, J. C., Lourenco, C., Alswaid, A., Bonnemann, C. G., and 15 others. Mutations in CSPP1 cause primary cilia abnormalities and Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. Am. J. Hum. Genet. 94: 62-72, 2014. Note: Erratum: Am. J. Hum. Genet. 94: 310 only, 2014. [PubMed: 24360808] [Full Text: https://doi.org/10.1016/j.ajhg.2013.11.019]


Contributors:
Cassandra L. Kniffin - updated : 2/11/2014

Creation Date:
Dorothy S. Reilly : 12/10/2007

Edit History:
alopez : 08/11/2015
mcolton : 7/31/2015
alopez : 2/9/2015
alopez : 2/25/2014
carol : 2/17/2014
mcolton : 2/12/2014
ckniffin : 2/11/2014
carol : 12/11/2007
wwang : 12/10/2007