Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency

• DOI: 10.1073/pnas.1417438111
• Publication Date: 2014-12-04T03:54:05Z
• Authors: Ravikumar Balasub...; Jin-Ho Choi; Ludmila Francescatto; Jason Willer; Edward R. Horton; Eleni P. Asimacop...; Konstantina M. St...; Lacey Plummer; Cassandra L. Buck; Richard Quinton; Todd D. Nebesio; Veronica Mericq; Paulina M. Merino; Brian F. Meyer; Dorota Monies; James F. Gusella; Nada Al Tassan; Nicholas Katsanis; William F. Crowley
• Keywords: 0301 basic medicine; CHARGE syndrome; Base Sequence; Molecular Sequence Data; Kallmann syndrome; DNA Helicases; Mutation, Missense; Kallmann Syndrome; Sequence Analysis, DNA; Protein Structure, Tertiary; CHD7; Idiopathic hypogonadotropic hypogondism; DNA-Binding Proteins; Gonadotropin-Releasing Hormone; Otolithic Membrane; 03 medical and health sciences; Phenotype; Gene Knockdown Techniques; Missense mutations; Animals; Humans; CHARGE Syndrome; Deficiency Diseases; Zebrafish

Significance

Inactivating mutations in the chromodomain helicase DNA binding protein 7 ( CHD7 ) gene causes a severe developmental disorder known as CHARGE syndrome. Recently, several missense mutations in CHD7 have been reported in isolated gonadotropin-releasing hormone (GnRH) -deficiency (IGD) patients who lack full CHARGE features. However, the precise functional consequence of these IGD-associated missense mutations on the activity of CHD7 protein is not known. This study confirms the predominance of missense CHD7 alleles in 5% of IGD patients and provides, to our knowledge, first experimental evidence that functionally compromised CHD7 missense alleles contribute to the pathogenesis of both the anosmic and normosmic forms of IGD. These results imply a preferential sensitivity for CHD7 dysfunction in the developmental ontogeny as well as neuroendocrine regulation of GnRH neurons in humans.