CCDC141 and Hypogonadotropic Hypogonadism

Congenital hypogonadotropic hypogonadism (HH) is characterized by deficient gonadotropin-releasing hormone (GnRH) secretion, resulting in pubertal failure and infertility. Oligogenic inheritance has been increasingly recognized in HH, with recent studies implicating CCDC141 variants as contributors. CCDC141 encodes a coiled-coil domain protein expressed in migrating GnRH neurons and olfactory fibers, essential for proper neuronal network formation.

Genetic evidence comes from multiple cohorts. In a study of 120 IHH/Kallmann syndrome families, inactivating CCDC141 variants were detected in 9 probands across four unrelated pedigrees, indicating a prevalence of 3.3% and supporting an autosomal recessive model ([PMID:28324054]). In a Tunisian KS family, homozygosity for c.2803C>T (p.Arg935Trp) in CCDC141 co-segregated with PROKR2 mutations in an AR digenic context ([PMID:34539727]).

Notably, unaffected father and brother homozygous for c.2803C>T remained asymptomatic, demonstrating incomplete penetrance and suggesting a requirement for additional genetic modifiers in disease expression ([PMID:34539727]).

Variant spectrum extends beyond KS. Five rare heterozygous CCDC141 variants—including c.163A>T (p.Ser55Cys) and c.3217G>A (p.Ala1073Thr)—were identified in 21 individuals from six families with self-limited delayed puberty, implicating haploinsufficiency in timing of pubertal onset ([PMID:34930920]).

Functional studies establish a clear mechanism of pathogenicity. Knockdown of Ccdc141 in mouse models impairs GnRH neuronal migration and olfactory fiber projection, recapitulating human KS features ([PMID:27014940]). In HEK293 cells, CCDC141 mutants mislocalize and disrupt microtubule acetylation, delaying cell migration ([PMID:34930920]). Zebrafish ccdc141 crispants exhibit ciliary defects and laterality abnormalities reversible by HDAC6 inhibition, underscoring a cilia–microtubule axis role ([PMID:39047937]).

Overall, the clinical validity of the CCDC141–HH association is Moderate, supported by nine probands in four families with segregation and robust functional concordance. CCDC141 acts in an autosomal recessive, oligogenic manner with incomplete penetrance. Functional data are Strong, demonstrating disrupted GnRH neuronal migration and ciliary function.

Key Take-home: CCDC141 variants disrupt GnRH neuron migration, contributing to hypogonadotropic hypogonadism and warranting inclusion in genetic testing panels for HH, especially in oligogenic presentations.

References

• Endocrinology • 2016 • CCDC141 Mutation Identified in Anosmic Hypogonadotropic Hypogonadism (Kallmann Syndrome) Alters GnRH Neuronal Migration. [PMID:27014940]
• The Journal of clinical endocrinology and metabolism • 2017 • CCDC141 Mutations in Idiopathic Hypogonadotropic Hypogonadism. [PMID:28324054]
• Frontiers in genetics • 2021 • Oligogenic Inheritance Underlying Incomplete Penetrance of PROKR2 Mutations in Hypogonadotropic Hypogonadism. [PMID:34539727]
• NPJ genomic medicine • 2021 • Whole exome sequencing identifies deleterious rare variants in CCDC141 in familial self-limited delayed puberty. [PMID:34930920]
• Journal of genetics and genomics = Yi chuan xue bao • 2024 • ccdc141 is required for left-right axis development by regulating cilia formation in the Kupffer's vesicle of zebrafish. [PMID:39047937]

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