Contribution of LHX4 mutations to pituitary deficits in a cohort of 417 unrelated patients

Context:LHX4 encodes a LIM-homeodomain transcription factor implicated in early pituitary development. In humans, only 13 heterozygous LHX4 mutations have been associated with congenital hypopituitarism.Objective:To evaluate the prevalence of LHX4 mutations in patients with hypopituitarism, and to precise the associated phenotypes. To characterize the functional impact of the identified variants and the respective role of the two LIM domains of LHX4.Patients and design:We screened 417 unrelated patients with isolated growth hormone deficiency or combined pituitary hormone deficiency associated with ectopic posterior pituitary and/or sella turcica anomalies for LHX4 mutations (Sanger sequencing). In vitro studies were performed to assess the functional consequences of the identified variants.Results:We identified seven heterozygous variations (p.(Tyr131*), p.(Arg48Thrfs*104), c.606+1G>T, p.Arg65Val, p.Thr163Pro, p.Arg221Gln, and p.Arg235Gln) associated with variable expressivity and, in five of them, incom...