Mutations in PROP1 cause familial combined pituitary hormone deficiency

Abstract

Combined pituitary hormone deficiency (CPHD) in man denotes impaired production of growth hormone (GH) and one or more of the other five anterior pituitary hormones. Mutations of the pituitary transcription factor gene POU1F1 (the human homologue of mouse Pit1) are responsible for deficiencies of GH, prolactin and thyroid stimulating hormone (TSH) in Snell and Jackson dwarf mice and in man, while the production of adrenocorticotrophic hormone (ACTH), luteinizing hormone (LH) and follicle stimulating hormone (FSH) is preserved. The Ames dwarf (df) mouse displays a similar phenotype, and appears to be epistatic to Snell and Jackson dwarfism. We have recently positionally cloned the putative Ames dwarf gene Prop1, which encodes a paired-like homeodomain protein that is expressed specifically in embryonic pituitary and is necessary for Pit1 expression. In this report, we have identified four CPHD families with homozygosity or compound heterozygosity for inactivating mutations of PROP1. These mutations in the human PROP1 gene result in a gene product with reduced DNA-binding and transcriptional activation ability in comparison to the product of the murine df mutation. In contrast to individuals with POU1F1 mutations, those with PROP1 mutations cannot produce LH and FSH at a sufficient level and do not enter puberty spontaneously. Our results identify a major cause of CPHD in humans and suggest a direct or indirect role for PROP1 in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes and caudomedial thyrotropes.

Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency

“…Because this mutation codifies a truncated protein with null function, it leads to a severe CPHD phenotype, affecting all the anterior pituitary hormones. The ACTH deficiency usually occurs in the third decade of life (17)(18)(19)23,25,39). In our cohort of patients, the older brother from family II presented a slightly compromised cortisol response to hypoglycemia (15.4 µg/dl) at the age of 11 years, and the patients from families I and III presented ACTH deficiency at the ages of 16 and 17 years (table 3).…”

“…The PROP1 358C>T (R120C) missense mutation identified in family V has never been described in Brazilian families, and only a few families of European, Mexican-American, and Jewish-Moroccan origins have been reported before (7,17,(41)(42)(43). The two brothers, born from a consanguineous marriage, developed progressive CPHD but were only diagnosed in adulthood (at 29 and 37 years of age).…”

“…The 301-302delAG mutation leads to a frame shift and a truncated PROP1 protein with null function. The 358C>T missense mutation predicts an amino acid change at codon 120 replacing a much conserved arginine by a cysteine (R120C) in the third helix of the DNA-binding domain of the PROP1, and the mutant protein has an eight-fold reduction in DNA binding affinity and impaired trans-activation activity (17). The mutation 296G>A predicts an amino acid change at codon 99 replacing a highly conserved arginine by a glutamine (R99Q) in the second helix of the paired DNA-binding homeodomain of PROP1.…”

“…HESX1 mutations cause either isolated GH deficiency or CPHD, associated or not with other anomalies such as septo-optic dysplasia and agenesis of the corpus callosum (5,9,10); LHX3 mutations lead to GH, TSH, PRL, and gonadotrophin deficiencies, associated with short cervical spine and limited neck rotation (11)(12)(13)(14); LHX4 mutations cause GH, TSH, and ACTH deficiencies and cerebellar abnormalities (15). Defects in PIT1 gene cause GH, TSH, and PRL deficiencies, and in PROP1 cause deficiencies in pituitary hormones produced by PIT1 dependent cell lineages (somatotrophs, thyrotrophs, lactotrophs), as well as evolving gonadotrophin and corticotrophin deficiencies (3,8,(16)(17)(18)(19).…”

Genética molecular do eixo hipotálamo-hipófise-gonadal

“…Até o momento, doze diferentes mutações, todas localizadas dentro do homeodomínio no PROP-1, foram identificadas em pacientes com hipopituitarismo (50)(51)(52)(53)(54)(55)(56). A mutação mais freqüentemente encontrada é a deleção AG 301,302, tanto em casos isolados quanto em famílias não relacionadas.…”