Journal Article Ahead of print
PubMed: 42554577 DOI: 10.1093/ejendo/lvag140
CCDC149: a novel gene associated with hypopituitarism and neurodevelopmental impairment.
Eur J Endocrinol
Authors: Louise C Gregory, Shoshana Rath, Hanna Mandel, Ghadir Elias Assad, Nadra N Samra, Arzo Iqbal, Stefania Pirosca, Michelle H Y Lam, Karin Weiss, Rinat Zaid, Julien Baruteau, Michael J Parker, Paul Dimitri, Sachin Deshpande, Naresh K Hanchate, Mehul T Dattani
Affiliations
- Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, United Kingdom.
- Tzafon Medical Center, affiliated with Azrieli Faculty of Medicine, Bar Ilan University, Poria, 1528001, Israel.
- Department of Genetics and Metabolic Disorders, Ziv Medical Center, Safed, 13100, Israel.
- Pediatric Endocrine Unit, Saint Vincent de Paul Hospital, Azrieli Faculty of Medicine, Bar Ilan University, Nazareth, 16102, Israel.
- The Genetics Institute, Rambam Health Care Campus, Haifa, 3109601, Israel.
- Sheffield Clinical Genomics Service, Sheffield Children's NHS Foundation Trust, Sheffield, S5 7 AU, United Kingdom.
- Department of Paediatric Endocrinology, Sheffield Children's NHS Foundation Trust, Sheffield, S5 7AT, United Kingdom.
Abstract
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. To date, only ∼10-15% of patients have an underlying molecular basis.
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.
MeSH
Genes, Growth, Neuroendocrinology, Brain, Hypopituitarism, Phenotype, Hormones, Pedigree, Neurodevelopment