Alternative titles; symbols
HGNC Approved Gene Symbol: CCDC141
Cytogenetic location: 2q31.2 Genomic coordinates (GRCh38) : 2:178,814,978-179,050,137 (from NCBI)
Based on experiments in mice, CCDC141 is predicted to play a role in centrosome positioning and movement during radial neuronal migration in developing nervous system (Fukuda et al., 2010).
Fukuda et al. (2010) cloned mouse Ccdc141, which they called Camdi. The deduced 1,451-amino acid protein has N-terminal spectrin (see 182860)-like repeats, a central coiled-coil domain, and I-set domains near the C terminus. Western blot analysis detected strong Camdi expression in embryonic day-16 mouse brain, but little to no expression in adult brain or 9 other adult mouse tissues examined. In situ hybridization detected Camdi expression in discrete cell layers of adult mouse cerebrum, hippocampus, and cerebellum, and in embryonic mouse eye. Database analysis detected orthologs of Camdi in humans and several vertebrates, but not in lower organisms.
Hutchins et al. (2016) analyzed Ccdc141 staining in mouse embryos and observed clear expression in migrating GnRH (152760) neurons. Robust Ccdc141 staining was also detected in the developing cortex as well as in cells and sensory axons of the peripheral nervous system such as the trigeminal and dorsal root ganglia.
Fukuda et al. (2010) reported that the CCDC141 gene maps to chromosome 2q31.
During late embryonic development in mouse, a massive number of cortical neurons undergo radial migration from the ventricular zone/subventricular zone through the intermediate zone toward the cortical plate. This directed migration is regulated by polarized movement of centrosomes toward the leading edge, often far in advance of nuclei, and requires the centrosomal protein Disc1 (605210) and phosphorylatable myosin light chain (MLC; see 613993). By yeast 2-hybrid analysis, Fukuda et al. (2010) found that mouse Camdi interacted with Disc1 and Mlc. Camdi and Disc1 colocalized to centrosomes, and Disc1 induced Camdi translocation to the centrosome. Disc1 interacted with Mlc in a Camdi-dependent manner, and coexpression of Camdi with Disc1 induced accumulation of phosphorylated Mlc near centrosomes. In utero knockdown of Camdi via RNA interference in embryonic mice resulted in abnormal cortical neuronal migration, leading to postnatal accumulation of neurons in the intermediate zone and reduced numbers of neurons at the cortical plate. Microscopic analysis of Camdi-knockdown neurons revealed disordered centrosomes and leading processes showing random orientation. Fukuda et al. (2010) concluded that CAMDI controls cortical neuronal migration, in part, through regulation of centrosome positioning in concert with DISC1.
By live imaging studies in mouse nasal explants, Hutchins et al. (2016) showed that GnRH neurons treated with Ccdc141-targeting siRNA had a 25% reduction in both linear and total migration rates compared to controls. Explants fixed at 5 divisions demonstrated that GnRH neurons in Ccdc141-knockdown explants did not migrate as far from the main tissue mass as in controls; however, olfactory axon growth was robust in control and Ccdc141 knockdown explants. GnRH neurons were closely apposed to olfactory exons in both the knockdown and control group, indicating that adhesion was not impaired by Ccdc141 knockdown and suggesting that defects in motility underlie the migration defects.
Associations Pending Confirmation
In 2 affected sibs from a consanguineous Kurdish family with anosmic hypogonadotropic hypogonadism (HH22; 616030), who were homozygous for a missense mutation in the FEZF1 gene (613301.0001), Kotan et al. (2014) also detected homozygosity for a nonsense mutation (R724X) in CCDC141. They noted that the CCDC141 gene product had been implicated in cortical neuronal migration and stated that this mutation might cause additional detrimental effects.
Turan et al. (2017) restudied the family originally reported by Kotan et al. (2014) (family 1) and described 3 new families in which 6 members had hypogonadotropic hypogonadism with a normal sense of smell. In family 2, a mother and son were compound heterozygous for missense mutations in CCDC141, and both also carried a heterozygous missense mutation in the DMXL2 gene (612186). In family 3, 2 affected and 2 unaffected family members were heterozygous for a missense mutation in CCDC141, and heterozygous missense mutations in 3 other genes (NR5A2, 604453; FSHB, 136530; IGSF10, 617351) were also detected in various combinations in both affected and unaffected family members. In family 4, an affected daughter inherited a heterozygous missense mutation in CCDC141 from her unaffected father. Clinical reversibility appeared to have occurred in 2 affected individuals from family 2 and 1 from family 3. Turan et al. (2017) stated that these families demonstrated complex, discordant genotype-phenotype relationships that were challenging to explain in terms of traditional mendelian inheritance.
Fukuda, T., Sugita, S., Inatome, R., Yanagi, S. CAMDI, a novel disrupted in schizophrenia 1 (DISC1)-binding protein, is required for radial migration. J. Biol. Chem. 285: 40554-40561, 2010. [PubMed: 20956536] [Full Text: https://doi.org/10.1074/jbc.M110.179481]
Hutchins, B. I., Kotan, L. D., Taylor-Burds, C., Ozkan, Y., Cheng, P. J., Gurbuz, F., Tiong, J. D. R., Mengen, E., Yuksel, B., Topaloglu, A. K., Wray, S. CCDC141 mutation identified in anosmic hypogonadotropic hypogonadism (Kallmann syndrome) alters GnRH neuronal migration. Endocrinology 157: 1956-1966, 2016. [PubMed: 27014940] [Full Text: https://doi.org/10.1210/en.2015-1846]
Kotan, L. D., Hutchins, B. I., Ozkan, Y., Demirel, F., Stoner, H., Cheng, P. J., Esen, I., Gurbuz, F., Bicakci, Y. K., Mengen, E., Yuksel, B., Wray, S., Topaloglu, A. K. Mutations in FEZF1 cause Kallmann syndrome. Am. J. Hum. Genet. 95: 326-331, 2014. [PubMed: 25192046] [Full Text: https://doi.org/10.1016/j.ajhg.2014.08.006]
Turan, I., Hutchins, I., Hacihamdioglu, B., Kotan, L. D., Gurbuz, F., Ulubay, A., Mengen, E., Yuksel, B., Wray, S., Topaloglu, A. K. CCDC141 mutations in idiopathic hypogonadotropic hypogonadism. J. Clin. Endocr. Metab. 102: 1816-1825, 2017. [PubMed: 28324054] [Full Text: https://doi.org/10.1210/jc.2016-3391]