Loss-of-function mutations in the immunoglobulin superfamily member 1 gene (IGSF1) cause a novel, X-linked syndrome of central hypothyroidism and testicular enlargement

Abstract

BackgroundCongenital central hypothyroidism occurs either as isolated thyroid-stimulating hormone (TSH) deficiency or in conjunction with other pituitary hormone deficits. Undetected central hypothyroidism is associated with developmental delay in children and adverse cardiometabolic sequelae in adults. Hitherto, mutations in the thyrotropin-releasing hormone receptor gene (TRHR) or the TSHb subunit gene (TSHB) are the only known causes of isolated TSH deficiency. MethodsUsing whole exome and candidate gene sequencing, we have studied 11 unrelated families with males exhibiting isolated TSH deficiency, testicular enlargement, and variably low serum prolactin levels. FindingsWe have identified eight distinct mutations and two whole gene deletions disrupting the X-linked immunoglobulin superfamily member 1 gene (IGSF1) in affected males. IGSF1 encodes a pituitary-enriched plasma membrane glycoprotein; disease-associated mutations block trafficking of IGSF1 from the endoplasmic reticulum to the membrane, consistent with loss-of-protein function. Adult male IGSF1 null mice exhibit central hypothyroidism with decreased pituitary TSH content and circulating T3 levels; TSH secretion in response to TRH is blunted and pituitary TRHR mRNA levels are decreased, suggesting that impaired TRH signalling may provide the basis for hypothyroidism. InterpretationOur observations delineate a novel X-linked syndrome in which loss-of-function mutations in IGSF1 cause central hypothyroidism, testicular enlargement, and variable prolactin deficiency, and identify a previously unsuspected role for IGSF1 in hypothalamic-pituitary control of thyroid and testicular function. Variable biochemical penetrance in these families highlights the importance of genetic ascertainment in this syndrome, so that asymptomatic affected individuals can benefit from early initiation of thyroxine treatment. FundingWellcome Trust and National Institute for Health Research Biomedical Research Centre.