Molecular Analysis ofLHX3andPROP-1in Pituitary Hormone Deficiency Patients with Posterior Pituitary Ectopia¹

Abstract

The cause of posterior pituitary ectopia associated with anterior pituitary hormone deficiencies is unknown. We describe children with combined pituitary hormone deficiency (CPHD) or isolated GH deficiency. In all cases, magnetic resonance imaging examination revealed abnormal pituitary gland development featuring ectopic posterior lobe location and frequently hypoplastic anterior lobes. Embryonic development of the pituitary requires the coordinated expression of specific transcription factors. Mutations of the PIT-1 and PROP-1 transcription factors are responsible for CPHD in some patients with normally positioned posterior pituitaries. In mice, the Lhx3 LIM homeodomain transcription factor is required for both structural development and cellular differentiation of the pituitary gland. Thus, we hypothesized that mutations in one or both of the two human LHX3 isoforms are responsible for posterior pituitary ectopia associated with anterior pituitary hypopituitarism. Comprehensive molecular analysis of the LHX3 isoforms was performed to test this hypothesis. No loss of function mutations in the LHX3 gene were detected. In addition, analysis of PROP-1 did not reveal mutations that might cause this phenotype. These studies suggest that the abnormal processes leading to the development of CPHD or GH deficiency associated with posterior pituitary ectopia are not a result of aberrant LHX3 or PROP-1 function, but may be caused by defects at other gene loci. (J Clin Endocrinol

High prevalence of PROP1 gene mutations in hungarian patients with childhood-onset combined anterior pituitary hormone deficiency

“…They found a strong association between an ectopic posterior pituitary and extrapituitary organ birth defects, but the potential significance of pituitary transcription factor mutations has not been investigated. Our study, together with some earlier observations indicate that PROP1 gene mutations are not involved in the pathomechanism of ectopic posterior pituitary (27,28).…”

NBPF9 Gene May Be Involved in Congenital Hypopituitarism: A Whole-Genome Study of a Boy with Pituitary Stalk Interruption Syndrome and His Family

“…We analyzed the reported genes LHX4, PROP1, CDON, TGIF, and PROKR2 in our study. LHX4/LHX3 are members of the LIM-homeobox family and regulate the proliferation and differentiation of pituitary lineages [1,2,12]. PROP1 is involved in early patterning, proliferation, positional determination, and terminal differentiation of the pituitary gland [4,13].…”

“…e database annotation, analysis, and global overview of variation were performed by ANNOVAR [8] and Variant Effect Predictor [9]. e genes SOX3, PROP1, LHX3, LHX4, HESX1, OTX2, PROKR2, TGIF, GPR161, and CDON have been analyzed in gene variation sets [1,2,[10][11][12][13].…”

Novel compound heterozygous variants in the LHX3 gene caused combined pituitary hormone deficiency: A case report

“…Combined pituitary hormone deficiency (CPHD) is an autosomal recessive inheritance genetic disease caused by mutation of the LHX3 gene. LHX3 mutations are associated with growth hormone (GH), gonadotropin, and thyroid-stimulating hormone (TSH) deficiency; abnormal pituitary morphology; and may be accompanied with limited neck rotation and sensorineural hearing loss[ 1 - 3 ].…”

“…The LHX3 gene, located on the subtelomeric region of chromosome 9 at band 9q34.3, consists of seven coding exons and six introns. It is a transcription factor and key regulator of pituitary development in early fetal life[ 1 ]. In this case, two novel heterozygous mutations of c.613G>C (p.V205L) and c.220T>C (p.C74R) in the LHX3 gene were found by whole-exosome sequencing (WES) in an 11-year-old patient with pituitary hormone deficiency, hydrocele of the tunica vaginalis, pituitary dwarfism, gonadal dysplasia, micropenis, clonic convulsion, and mild facial dysmorphic features.…”