Alternative titles; symbols
HGNC Approved Gene Symbol: CEP135
Cytogenetic location: 4q12 Genomic coordinates (GRCh38) : 4:55,948,945-56,033,361 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q12 | Microcephaly 8, primary, autosomal recessive | 614673 | Autosomal recessive | 3 |
CEP135, SASS6 (609321), and CPAP (CENPJ; 609279) make up an ancestral module that forms the core centriole and basal body structure with 9-fold symmetry. CEP135 has a critical function in early centriole and basal body assembly (summary by Carvalho-Santos et al., 2010).
By sequencing clones obtained from a size-fractionated brain cDNA library, Ishikawa et al. (1998) cloned CEP135, which they designated KIAA0635. The transcript contains repetitive elements at both the 5-prime and 3-prime UTRs, and the deduced protein contains 846 amino acids. RT-PCR detected variable CEP135 expression in all tissues examined, with highest expression in kidney, testis, and ovary, and lowest expression in brain and spleen.
Using mass spectrometry and proteomics to identify protein components of interphase centrosomes isolated from a human lymphoblastic cell line, Andersen et al. (2003) identified CEP135 as a centrosomal component. The predicted molecular mass was 135 kD. Imaging confirmed that fluorescence- and epitope-tagged CEP135 localized to centrosomes in a human osteoblastoma cell line.
Hussain et al. (2012) stated that the open reading frame of the CEP135 gene consists of 1,140 amino acids.
Carvalho-Santos et al. (2010) reported that CEP135 contains long coiled-coil domains. By database analysis, they identified N- and C-terminal domains within the coiled-coil regions that were conserved in vertebrates. Orthologs of CEP135 were not detected in several invertebrates.
Hussain et al. (2012) stated that the CEP135 gene contains 26 exons.
By radiation hybrid analysis, Ishikawa et al. (1998) mapped the CEP135 gene to chromosome 4.
Hussain et al. (2012) stated that the CEP135 gene maps to chromosome 4q12.
Using a salt extraction technique with purified human centrioles, Andersen et al. (2003) showed that CEP135 is a centrosomal scaffold protein.
Through siRNA-mediated depletion and immunoelectron microscopy directed to individual centrosomal proteins, Kleylein-Sohn et al. (2007) found that CEP135, PLK4 (605031), SAS6 (609321), CPAP (CENPJ; 609279), TUBG1 (191135), and CP110 (609544) were required at different stages of procentriole formation and were associated with different centriolar structures. SAS6 associated only transiently with nascent procentrioles, whereas CEP135 and CPAP formed a core structure within the proximal lumen of both parental and nascent centrioles.
Primary Microcephaly 8, Autosomal Recessive
In 2 sibs, born of consanguineous Pakistani parents, with autosomal recessive primary microcephaly-8 (MCPH8; 614673) and severe mental retardation, Hussain et al. (2012) identified a homozygous truncating mutation in the CEP135 gene (611423.0001). The mutation was identified by genomewide linkage analysis followed by candidate gene sequencing, and was not found in 384 Pakistani controls. Whole-exome sequencing of 1 of the patients did not identify other potentially pathogenic mutations that could be responsible for the disorder. Analysis of the CEP135 gene in 7 other families from this region with primary microcephaly did not identify any additional mutations. Patient fibroblasts from one of the patients showed multiple fragmented centrosomes, disorganized microtubules, and reduced growth rate. The findings indicated that CEP135 is an essential component of the centrosome.
In 2 sibs, born of consanguineous Pakistani parents, with MCPH8, Farooq et al. (2016) identified a homozygous splice site mutation in the CEP135 gene (611423.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was predicted to result in nonsense-mediated mRNA decay, but even if translated the mutant protein would lack the C-terminal hSAS-6 interacting domain, most likely leading to multiple and fragmented centrosomes with disorganized microtubules.
Associations Pending Confirmation
For discussion of a possible association between variation in the CEP135 gene and spermatogenic failure, see 611423.0003.
In 2 sibs, born of consanguineous Pakistani parents, with autosomal recessive primary microcephaly-8 (MCPH8; 614673), Hussain et al. (2012) identified a homozygous 1-bp deletion (970delC) in exon 8 of the CEP135 gene, resulting in a frameshift and premature termination (Gln324SerfsTer2). The mutant transcript was demonstrated to undergo partial nonsense-mediated mRNA decay. The mutation was identified by genomewide linkage analysis followed by candidate gene sequencing, and was not found in 384 Pakistani controls. Whole-exome sequencing of 1 of the patients did not identify other potentially pathogenic mutations that could be responsible for the disorder. The parents were healthy with normal head circumference; the father carried the mutation in heterozygous state. Cultured patient fibroblasts showed poor growth and had increased numbers of fragmented centrosomes per cell compared to controls. The microtubule network was frequently disorganized (55% of the cells) and showed cell shape changes as well as misshapen and fragmented nuclei. Approximately 22% of mutant patient fibroblasts were without centrosomes, which was never observed in control cells. In vitro functional expression studies of the mutant protein in COS-7 cells caused abnormal disorganized microtubule networks and the mutant protein did not localize to the centrosome.
In 2 sibs, born of consanguineous Pakistani parents, with autosomal recessive primary microcephaly-8 (MCPH8; 614673), Farooq et al. (2016) identified a homozygous G-to-A transition in intron 11 of the CEP135 gene (c.1473+1G-A), resulting in a splice site alteration. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was filtered against the dbSNP (build 138) database, and was not found in the Exome Variant Server or ExAC databases, or in 200 Pakistani controls. Transfection of the mutation into HEK293 cells showed that it resulted in the skipping of exon 11, a frameshift, and premature termination (Glu417GlyfsTer2) and possible nonsense-mediated mRNA decay, consistent with a loss of function. Even if translated into a truncated protein, the mutant protein would lack the C-terminal hSAS-6 interacting domain, most likely leading to multiple and fragmented centrosomes with disorganized microtubules.
This variant is classified as a variant of unknown significance because its contribution to spermatogenic failure has not been confirmed.
In an infertile 30-year-old Han Chinese man with spermatogenic failure due to multiple morphologic abnormalities of the flagella (MMAF), Sha et al. (2017) performed whole-exome sequencing and identified homozygosity for a c.1364A-T transversion (c.1364A-T, NM_025009) in exon 11 of the CEP135 gene, resulting in an asp455-to-val (D455V) substitution at a highly conserved residue. His unaffected consanguineous parents were heterozygous for the mutation. Semen analysis in the patient showed severely reduced motility and vitality, as well as features of MMAF, with only 0.5% normal spermatozoa. Approximately 85% of patient sperm exhibited short or absent flagella, and 46% had flagella of an irregular caliber; other abnormalities included coiled (12%) or angulated (3%) flagella. Immunofluorescence analysis showed localization of CEP135 to the sperm centriole in wildtype controls, whereas in patient sperm CEP135 was expressed at lower levels in the centriole compared to controls, with ectopic aggregates accumulating in the flagella near the centrosome. In vitro fertilization attempts, involving transfer of 3 embryos on 2 occasions, were unsuccessful. The authors noted that the proband did not exhibit primary microcephaly or respiratory disease.
Andersen, J. S., Wilkinson, C. J., Mayor, T., Mortensen, P., Nigg, E. A., Mann, M. Proteomic characterization of the human centrosome by protein correlation profiling. Nature 426: 570-574, 2003. [PubMed: 14654843] [Full Text: https://doi.org/10.1038/nature02166]
Carvalho-Santos, Z., Machado, P., Branco, P., Tavares-Cadete, F., Rodrigues-Martins, A., Pereira-Leal, J. B., Bettencourt-Dias, M. Stepwise evolution of the centriole-assembly pathway. J. Cell Sci. 123: 1414-1426, 2010. [PubMed: 20392737] [Full Text: https://doi.org/10.1242/jcs.064931]
Farooq, M., Fatima, A., Mang, Y., Hansen, L., Kjaer, K. W., Baig, S. M., Larsen, L. A., Tommerup, N. A novel splice site mutation in CEP135 is associated with primary microcephaly in a Pakistani family. J. Hum. Genet. 61: 271-273, 2016. [PubMed: 26657937] [Full Text: https://doi.org/10.1038/jhg.2015.138]
Hussain, M. S., Baig, S. M., Neumann, S., Nurnberg, G., Farooq, M., Ahmad, I., Alef, T., Hennies, H. C., Technau, M., Altmuller, J., Frommolt, P., Thiele, H., Noegel, A. A., Nurnberg, P. A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function. Am. J. Hum. Genet. 90: 871-878, 2012. [PubMed: 22521416] [Full Text: https://doi.org/10.1016/j.ajhg.2012.03.016]
Ishikawa, K., Nagase, T., Suyama, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5: 169-176, 1998. [PubMed: 9734811] [Full Text: https://doi.org/10.1093/dnares/5.3.169]
Kleylein-Sohn, J., Westendorf, J., Le Clech, M., Habedanck, R., Stierhof, Y.-D., Nigg, E. A. Plk4-induced centriole biogenesis in human cells. Dev. Cell 13: 190-202, 2007. [PubMed: 17681131] [Full Text: https://doi.org/10.1016/j.devcel.2007.07.002]
Sha, Y.-W., Xu, X., Mei, L.-B., Li, P., Su, Z.-Y., He, X.-Q., Li, L. A homozygous CEP135 mutation is associated with multiple morphological abnormalities of the sperm flagella (MMAF). Gene 633: 48-53, 2017. [PubMed: 28866084] [Full Text: https://doi.org/10.1016/j.gene.2017.08.033]