ECEESPE2025 Rapid Communications Rapid Communications 10: Pituitary, Neuroendocrinology and Puberty Part 2 (6 abstracts)
Recessive truncations in a previously uncharacterized gene, CCDC149, are a novel cause of congenital hypopituitarism
Louise Gregory 1 , Shoshana Rath 2 , Hanna Mandel 3 , Ghadir Elias-Assad 4 , Nadra Samra 3 , Michael Parker 5 , Paul Dimitri 6 , Naresh Hanchate 1 & Mehul Dattani 1
1UCL Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine Research and Teaching Department, London, United Kingdom; 2Tzafon Medical Center, Bar -Ilan University, Azrieli Faculty of Medicine, Nazareth, Israel; 3Ziv Medical Center, Department of Genetics and Metabolic Disorders, Safed, Israel; 4Saint Vincent de Paul Hospital, Bar -Ilan University, Pediatric endocrine unit, Azrieli Faculty of Medicine, Nazareth, Israel; 5Sheffield Children’s NHS Foundation Trust, Sheffield Clinical Genomics Service, Sheffield, United Kingdom; 6Sheffield Children’s NHS Foundation Trust, Department of Paediatric Endocrinology, Sheffield, United Kingdom
JOINT645
Background: Congenital Hypopituitarism (CH) is a complex developmental disorder characterized by a variable combination of defects in pituitary function, including deficiencies in growth hormone (GHD) (most frequent), gonadotropins, ACTH, TSH, prolactin and vasopressin. To date, a molecular basis has been identified in ~10-15 % of patients, but the majority remain unexplained.
Methods: Next generation sequencing was performed in two unrelated pedigrees including three patients with GHD, hypogonadotropic hypogonadism, and developmental delay/autism. MRI studies were performed to visualize morphological defects in the spinal cord and the pituitary. In situ hybridisation was conducted to generate an expression profile of CCDC149 in the human embryonic brain at different Carnegie stages of development. A null Ccdc149 mouse model was generated for phenotypic characterization.
Results
Two novel homozygous frameshifts were identified in CCDC149, c.832G>T p.G278* and c.665T>A, p.L222* respectively, in the two unrelated pedigrees with CH. Severe scoliosis was present in two out of the three patients, with the third unrelated patient having a small anterior pituitary on MRI. CCDC149 mutations have not been reported previously. Human embryonic expression of CCDC149 was localised to the developing hypothalamo-pituitary (HP) region at Carnegie stages (CS) 16, 19, 20 and 23. Preliminary murine data suggest that Ccdc149-knockout mice exhibit growth impairment and reduced fertility compared to their wildtype littermates.
Conclusion
We report the first genetic variant in a novel gene, CCDC149, associated with CH, scoliosis and learning difficulties/autism. We present clinical and molecular data in two pedigrees with CH, as well as gene expression in human embryonic sections and murine data to confirm the association between CCDC149 variations and CH. CCDC149 is therefore a novel candidate gene that should be considered for analysis in patients with unsolved CH. Previous studies in C.elegans report expression of the CCDC149 orthologue in the basal bodies of ciliated neurons, supporting the possibility of impaired ciliary function as an underlying mechanism in this complex disorder.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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