Investigation of new candidate genes in a cohort of patients with familial congenital hypopituitarism and associated disorders

摘要: Congenital hypopituitarism is a complex variable genetic disorder that known to be caused by multiple mutated genes, both in isolation and variably penetrant cases of digenic inheritance. In only <10% cases, mutation causative gene has been identified the patient, leaving vast majority patients yet have detected responsible for pathogenicity functional significance their condition. This study investigates novel genes pathways involved hypothalamo-pituitary development. Our large cohort consanguineous non-consanguineous pedigrees with disease are routinely screened variants genes. where there no these particular exome sequencing collaboration GOSgene carried out uncover regions interest abnormal individual. Upon identification any variant or assays conducted further show change. Firstly this identifies first homozygous LHX4 gene, p.T126M, two deceased brothers from pedigree combined pituitary hormone deficiency subsequent fatal consequences. Functional luciferase showed was significant difference between mutant p.T126M WT constructs transactivating αGSU prolactin promoters, could synergise POU1F1 similar LHX4. Secondly, six new candidate genes; CTPS2, RNPC3, PRMT6, FASN, APEX2 EIF2S3, were phenotypically unique submitted sequencing. The human embryonic expression profiles analysed context, as well related tissues affected individuals. Thirdly, role eIF2γ, encoded which found an X-linked congenital hypopituitarism, hypothyroidism hyperinsulinism causing hypoglycaemia, investigated study. A lentiviral shRNA knock EIF2S3 pancreatic cells resulted significantly higher apoptosis compared cells. used Sanger approach identify respectively.