Three Novel Missense Mutations within the LHX4 Gene Are Associated with Variable Pituitary Hormone Deficiencies

Abstract

Context:The LHX4 LIM-homeodomain transcription factor has essential roles in pituitary gland and nervous system development. Heterozygous mutations in LHX4 are associated with combined pituitary hormone deficiency.Objectives: Our objectives were to determine the nature and frequency of LHX4 mutations in patients with pituitary hormone deficiency and to examine the functional outcomes of observed mutations. Design:The LHX4 gene sequence was determined from patient DNA. The biochemical and gene regulatory properties of aberrant LHX4 proteins were characterized using structural predictions, pituitary gene transcription assays, and DNA binding experiments. Patients:A total of 253 patients from 245 pedigrees with GH deficiency and deficiency of at least one additional pituitary hormone was included in the study. Results:In five patients, three types of heterozygous missense mutations in LHX4 that result in substitution of conserved amino acids were identified. One substitution is between the LIM domains (R84C); the others are in the homeodomain (L190R; A210P). The patients have GH deficiency; some also display reductions in TSH, LH, FSH, or ACTH, and aberrant pituitary morphology. Structural models predict that the aberrant L190R and A210P LHX4 proteins would have impaired DNA binding and gene activation properties. Consistent with these models, EMSAs and transfection experiments using pituitary gene promoters demonstrate that whereas the R84C form has reduced activity, the L190R and A210P proteins are inactive. A fter early inductive events, the development of the specialized hormone-secreting cells of the anterior pituitary gland is dependent on the actions of multiple transcription factors such as LHX3, LHX4, PIT1 (POU1F1 gene), PROP1, PITX1, PITX2, SF1, and TPIT (1). Of these, the structurally related LHX3 and LHX4 proteins are members of the LIMhomeodomain (HD) family of transcription factors (2). LIM-HD proteins feature two amino-terminal LIM domains, required for Conclusions

Transcription factor 7-like 1 is involved in hypothalamo–pituitary axis development in mice and humans

“…Additionally, mutations in SHH and GLI2, a mediator of SHH, are associated with variably penetrant holoprosencephaly. Sequence variants in LHX4 and GLI2 are also associated with variably penetrant CH (63,64). Of note, variable phenotypic expressivity is also observed in the Hesx1 Cre/+ ;Tcf7l1 fl/− mouse mutants and in the tcf7l1a −/− ;tcf3l1b +/− zebrafish mutants injected with the hTCF7L1 variants identified in this study.…”

ANE syndrome caused by mutated RBM28 gene: a novel etiology of combined pituitary hormone deficiency

“…These genes are HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2, SOX3, TBCE, and OTX2 (4-6). Non-syndromic CPHD has been found to be caused by mutations in PROP1 and POU1F1 (7-9), while mutations in the other genes typically cause a syndromic subtype of CPHD, featuring septo-optic dysplasia (HESX1) (10), short stiff neck (LHX3) (11), cerebellar anomalies (LHX4) (12,13), mental retardation (SOX3) (14), anophthalmia, esophageal atresia, and genital anomalies (SOX2) (15,16), hypoparathyroidism-retardation and dysmorphism (TBCE) (5), and microphthalmia and anophthalmia (OTX2) (6). Associated neuroradiological findings, including anterior pituitary hypoplasia, absent infundibulum, and an ectopic posterior pituitary, may present in 50% of patients with CPHD (4).…”

A novel 12 bp deletion within goat <i>LHX4</i> gene significantly affected litter size

“…These hormones regulate growth and metabolism, reproductive development, and so on in humans and livestock (Mullena et al, 2007). Deficiency of the LHX4 and other genes (such as LHX3, and Pitx2) renders combined pituitary hormone deficiency (CPHD) and pituitary hypoplasia in both humans and mice (Raetzman et al, 2002;Hunter and Rhodes, 2005;Pfaeffle et al, 2008), suggesting that the LHX4 gene has a significant influence on stimulating the rapid proliferation of undifferentiated pituitary progenitors via activating LHX3 and maintaining expression of Pitx2 in mice (Gergics et al, 2015). Moreover, the mutations of the LHX4 gene are also associated with dominantly inherited GH deficiency.…”