CCDC149: a novel gene associated with hypopituitarism and neurodevelopmental impairment

06/08/2026

AI Summary

Biallelic CCDC149 frameshift mutations (p.Gly278* and p.Leu222*) identified in two unrelated pedigrees, implicating CCDC149 as a novel gene for congenital hypopituitarism.
Affected patients showed growth hormone deficiency, hypogonadotropic hypogonadism and neurodevelopmental impairment; MRI and skeletal findings included small anterior pituitary and severe scoliosis.
CCDC149 localised to human embryonic hypothalamo-pituitary region; Ccdc149-null mice phenocopied human features, supporting impaired ciliary function as a putative mechanism.

AI Summary

OBJECTIVE & DESIGN: Congenital Hypopituitarism (CH) is a complex developmental disorder characterized by variable pituitary dysfunction that is often associated with midline structural abnormalities that affect the brain, eyes and face.

Human embryonic CCDC149 was localised to the developing hypothalamo-pituitary region at Carnegie stages 16-23, and Ccdc149-null mice recapitulated patient phenotypes, including growth impairment and reduced fertility compared to wild-type littermates.

Previous studies in C.elegans report CCDC149 orthologue expression in the basal bodies of ciliated neurons, supporting the possibility of impaired ciliary function as an underlying mechanism in this complex disorder.

Basic summary

Eur J Endocrinol. 2026 Aug 5:lvag140. doi: 10.1093/ejendo/lvag140. Online ahead of print.

ABSTRACT

METHODS: Next generation sequencing was conducted on a subset of CH patients with no known genetic aetiology. Human embryonic brain tissue sections were used to generate an expression profile, and a knock-out mouse model was generated using CRISPR-Cas9 gene editing and phenotypically analysed.

RESULTS: Two novel homozygous frameshifts in CCDC149, p.Gly278* and p.Leu222*, were identified in two unrelated CH pedigrees (three patients), respectively. Patient phenotypes included growth hormone deficiency (GHD), hypogonadotropic hypogonadism, and developmental delay/autism. Severe scoliosis was present in one pedigree, with a small anterior pituitary on MRI in the other. Human embryonic CCDC149 was localised to the developing hypothalamo-pituitary region at Carnegie stages 16-23, and Ccdc149-null mice recapitulated patient phenotypes, including growth impairment and reduced fertility compared to wild-type littermates.

CONCLUSIONS: Our study is the first to report CCDC149 variants in association with CH. Previous studies in C.elegans report CCDC149 orthologue expression in the basal bodies of ciliated neurons, supporting the possibility of impaired ciliary function as an underlying mechanism in this complex disorder.

PMID:42554577 | DOI:10.1093/ejendo/lvag140

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