Alternative titles; symbols
HGNC Approved Gene Symbol: CEP41
Cytogenetic location: 7q32.2 Genomic coordinates (GRCh38) : 7:130,393,771-130,441,741 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q32.2 | Joubert syndrome 15 | 614464 | Autosomal recessive | 3 |
Using genomic sequence analysis of a PAC/BAC contig containing the imprinted MEST (601029) gene, followed by EST database searching, Yamada et al. (2002) identified cDNAs corresponding to 2 splice variants of TSGA14 encoding deduced proteins of 373 and 54 amino acids. Northern blot analysis detected transcripts of the longer isoform in adult testis (1.4 and 3.7 kb) and in fetal brain, lung, liver, and kidney (3.7 and 2.9 kb). A 1.1-kb transcript of the shorter isoform was weakly expressed in adult testis and fetal tissues. Using methylation analysis of a CpG island in TSGA14 intron 1 and analysis of biallelic expression of an exon 1 SNP in fetal tissues and blood lymphocytes, Yamada et al. (2002) showed that TSGA14 escapes genomic imprinting. Yamada et al. (2002) suggested that the 7q32 imprinted region may be small compared to other imprinted domains.
In zebrafish, Lee et al. (2012) found Cep41 expression in various ciliary organs, including Kupffer vesicle, ear, heart, brain, and kidney. Cep41 was also found in the centrioles and cilia of several ciliated cell lines, including mouse inner medullary collecting duct cells and human retinal pigment epithelial cells.
Yamada et al. (2002) determined that the TSGA14 gene contains 11 exons and spans approximately 50 kb. The short variant is encoded by 3 exons, the first 2 exons in common with the long variant and a third exon located in intron 2 of the long variant.
By genomic sequence analysis, Yamada et al. (2002) mapped the TGSA14 gene to chromosome 7q32 at a position 50 kb proximal to the MEST gene in a head to head orientation.
In affected members of 3 consanguineous families with Joubert syndrome-15 (JBTS15; 614464), 2 of Egyptian origin and 1 Portuguese, Lee et al. (2012) identified 3 different homozygous mutations in the CEP41 gene (610523.0001-610523.0003). The first mutation was found by linkage analysis followed by candidate gene sequencing in 1 of the families. Heterozygous CEP41 mutations (see, e.g., 610523.0004-610523.0007) were found in 5 additional patients with Joubert syndrome, and 3 of them were found to carry heterozygous mutations in other genes associated with ciliopathies (KIF7; 611254.0007 and CC2D2A; 612013.0007 and 612013.0009). These findings indicated digenic inheritance, and suggested that CEP41 may act as a modifier in the broader class of ciliopathies. Primary cultured fibroblasts from patients showed lack of CEP41 protein. Induction of ciliogenesis in these fibroblast resulted in cilia with a reduction of staining for GT335, which recognizes the glutamylated forms of tubulin. Forced expression of CEP41 increased the percentage of cells with glutamylated cilia. These findings suggested a potential role of CEP41 in regulating the posttranslational modification of tubulin by glutamylation. The cilia of zebrafish deficient in Cep41 showed a defect in tubulin structural defects, as well as defects in motility. Only the axoneme appeared to be affected, with the centriole being properly modified. Further studies in zebrafish and mouse cells indicated that Cep41 functions by mediating transport of TTLL6 (610849), an evolutionarily conserved polyglutamylase enzyme, between the basal body and cilium. The findings implicated tubulin posttranslational modification in the pathogenesis of human ciliary dysfunction.
Lee et al. (2012) demonstrated that morpholino knockout of Cep41 in zebrafish resulted in peripheral heart edema and tail defects, along with ciliopathy-related phenotypes, including hydrocephalus, abnormal ear otolith formation, and small eyes. Transfection of human CEP41 resulted in partial rescue of the phenotype. Specific knockout of Cep41 in zebrafish myocardium resulted in inversion defects or failure to develop asymmetry of the ventricle and atrium, suggesting a role in heart laterality. Homozygous Cep41 mouse mutants showed a wide range of phenotypes, including malformed hindbrain, exencephaly, brain hemorrhage, dilated pericardial sac, and lethality. However, some homozygous mutants showed normal development, suggesting the presence of extragenic phenotypic modifiers. The cilia of zebrafish deficient in Cep41 showed a defect in tubulin glutamylation, and electron microscopy showed structural defects in zebrafish renal cilia, with the A-tubules of the outer doublet microtubules of the axoneme being collapsed and/or duplicated. The cilia of the Kupffer vesicle and kidney showed disabled motility. The data suggested that Cep41 is involved in ciliary structural formation and motility by having an essential role in tubulin glutamylation at the cilium.
In 5 affected members of a consanguineous Egyptian family with Joubert syndrome-15 (JBTS15; 614464), Lee et al. (2012) identified a homozygous T-to-G transversion in intron 1 of the CEP41 gene (33+2T-G). Studies of patient cells showed absence of mature CEP41 mRNA, probably a result of nonsense-mediated mRNA decay. The mutation was found by linkage analysis followed by candidate gene sequencing. The patients had hypotonia, ataxia, psychomotor delay with borderline or mild mental retardation, and the molar tooth sign on brain imaging. One of the patients had a more severe phenotype, with unilateral retinopathy, coloboma, nephronophthisis, mild liver abnormalities, postaxial polydactyly, and ambiguous genitalia, and died at age 7 days. The other 4 patients did not have liver or renal involvement.
In 2 sisters, born of consanguineous Egyptian parents, with Joubert syndrome (JBTS15; 614464), Lee et al. (2012) identified a homozygous 3-bp deletion (97+3_5delGAG) predicted to abolish the donor splice site from exon 2. The mutation was demonstrated to cause skipping of exon 2 and premature termination in exon 3. The girls had hypotonia, ataxia, mental retardation, oculomotor apraxia, breathing abnormalities, and molar tooth sign on brain imaging, but no renal or liver involvement. One had unilateral postaxial polydactyly. A third sib, a boy, who did not have the molar tooth sign, was found to be heterozygous for the mutation.
In a patient, born of consanguineous Portuguese parents, with Joubert syndrome (JBTS15; 614464), Lee et al. (2012) identified a homozygous A-to-C transversion (423-2A-C), predicted to abolish the splice acceptor site from exon 7. The patient had hypotonia, ataxia, mental retardation, retinopathy, polydactyly, and the molar tooth sign on brain imaging. He did not have renal or hepatic involvement. He was also found to carry a heterozygous mutation in the CEP290 gene (610142).
In a German patient with digenic inheritance of Joubert syndrome, Lee et al. (2012) identified a heterozygous 536A-G transition in exon 7 of the CEP41 gene, resulting in an arg179-to-his (R179H) substitution in a highly conserved residue consistent with JBTS15 (614464), and a heterozygous truncating mutation in the KIF7 gene (811delG; 611254.0007), consistent with JBTS12 (see 200990). He had hypotonia, ataxia, mental retardation, oculomotor apraxia, breathing abnormalities, and the molar tooth sign on brain imaging, but no liver, renal, or retinal involvement.
In a Spanish patient with digenic inheritance of Joubert syndrome, Lee et al. (2012) identified a heterozygous 107T-C transition in exon 3 of the CEP41 gene, resulting in a met36-to-thr (M36T) substitution in a highly conserved residue consistent with JBTS15 (614464), and a heterozygous mutation in the CC2D2A gene (R1049X; 612013.0007), consistent with JBTS9 (612285). She had hypotonia, ataxia, mental retardation, and the molar tooth sign on brain MRI, but no liver, renal, or retinal involvement.
In a Swiss patient with digenic inheritance of Joubert syndrome, Lee et al. (2012) identified a heterozygous 1078C-T transition in exon 11 of the CEP41 gene resulting in an arg360-to-cys (R360C) substitution in a conserved residue consistent with JBTS15 (614464), and a heterozygous mutation in the CC2D2A gene (E1447A; 612013.0009), predicted to be a potentially deleterious sequence variant and consistent with JBTS9 (612285). She had hypotonia, ataxia, mental retardation, oculomotor apraxia, bilateral preaxial polydactyly, and the molar tooth sign on brain MRI, but no liver, renal, or retinal involvement.
In an Italian patient with Joubert syndrome (JBTS15; 614464), Lee et al. (2012) identified a heterozygous 83C-A transversion in exon 2 of the CEP41 gene, resulting in a ser28-to-ter (S28X) substitution. A second pathogenic mutation was not identified. The patient had hypotonia, ataxia, mental retardation, oculomotor apraxia, breathing difficulties, and the molar tooth sign on brain MRI, but no liver, renal, or retinal involvement.
Lee, J. E., Silhavy, J. L., Zaki, M. S., Schroth, J., Bielas, S. L., Marsh, S. E., Olvera, J., Brancati, F., Iannicelli, M., Ikegami, K., Schlossman, A. M., Merriman, B., and 18 others. CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium. Nature Genet. 44: 193-199, 2012. [PubMed: 22246503] [Full Text: https://doi.org/10.1038/ng.1078]
Yamada, T., Kayashima, T., Yamasaki, K., Ohta, T., Yoshiura, K., Matsumoto, N., Fujimoto, S., Niikawa, N., Kishino, T. The gene TSGA14, adjacent to the imprinted gene MEST, escapes genomic imprinting. Gene 288: 57-63, 2002. [PubMed: 12034494] [Full Text: https://doi.org/10.1016/s0378-1119(02)00428-6]