The PROP1 2-Base Pair Deletion Is a Common Cause of Combined Pituitary Hormone Deficiency1

Combined pituitary hormone deficiency (CPHD) has an incidence of approximately 1 in 8000 births. Although the proportion of familial CPHD cases is unknown, about 10% have an affected first degree relative. We have recently reported three mutations in the PROP1 gene that cause CPHD in human subjects. We report here the frequency of one of these mutations, a 301–302delAG deletion in exon 2 of PROP1, in 10 independently ascertained CPHD kindreds and 21 sporadic cases of CPHD from 8 different countries. Our results show that 55% (11 of 20) of PROP1 alleles have the 301–302delAG deletion in familial CPHD cases. Interestingly, although only 12% (5 of 42) of the PROP1 alleles of our 21 sporadic cases were 301–302delAG, the frequency of this allele (in 20 of 21 of the sporadic subjects given TRH stimulation tests) was 50% (3 of 6) and 0% (0 of 34) in the CPHD cases with pituitary and hypothalamic defects, respectively. Using whole genome radiation hybrid analysis, we localized the PROP1 gene to the distal end of chromosome 5q and identified a tightly linked polymorphic marker, D5S408, which can be used in segregation studies. Analysis of this marker in affected subjects with the 301–302delAG deletion suggests that rather than being inherited from a common founder, the 301–302delAG may be a recurring mutation.

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A Novel LHX3 Mutation Presenting as Combined Pituitary Hormonal Deficiency

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2005-2360 ◽

2006 ◽

Vol 91 (3) ◽

pp. 747-753 ◽

Cited By ~ 71

Author(s):

Amrit P. S. Bhangoo ◽

Chad S. Hunter ◽

Jesse J. Savage ◽

Henry Anhalt ◽

Steven Pavlakis ◽

...

Keyword(s):

Cervical Spine ◽

Novel Mutation ◽

Laboratory Data ◽

Nervous System Development ◽

In Vitro Translation ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Free T4 ◽

Exon 2 ◽

Base Pair Deletion

Abstract Context: LHX3 encodes LIM homeodomain class transcription factors with important roles in pituitary and nervous system development. The only previous report of LHX3 mutations described patients with two types of recessive mutations displaying combined pituitary hormone deficiency coupled with neck rigidity. Objective: We report a patient presenting a unique phenotype associated with a novel mutation in the LHX3 gene. Patient: We report a 6-yr, 9-month-old boy born from a consanguineous relationship who presented shortly after birth with cyanosis, feeding difficulty, persistent jaundice, micropenis, and poor weight gain and growth rate. Laboratory data, including an undetectable TSH, low free T4, low IGF-I and IGF binding protein-3, prolactin deficiency, and LH and FSH deficiency were consistent with hypopituitarism. A rigid cervical spine leading to limited head rotation was noticed on follow-up examination. Magnetic resonance imaging revealed an apparently structurally normal cervical spine and a postcontrast hypointense lesion in the anterior pituitary. Results: Analysis of the LHX3 gene revealed homozygosity for a novel single-base-pair deletion in exon 2. This mutation leads to a frame shift predicted to result in the production of short, inactive LHX3 proteins. The results of in vitro translation experiments are consistent with this prediction. The parents of the patients are heterozygotes, indicating a recessive mode of action for the deletion allele. Conclusions: The presence of a hypointense pituitary lesion and other clinical findings broadens the phenotype associated with LHX3 gene mutation.

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Functional SNPs within the Intron 1 of the PROP1 Gene Contribute to Combined Growth Hormone Deficiency (CPHD)

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2012-1527 ◽

2012 ◽

Vol 97 (9) ◽

pp. E1791-E1797 ◽

Cited By ~ 3

Author(s):

Michela Godi ◽

Simona Mellone ◽

Luigi Tiradani ◽

Rita Marabese ◽

Claudio Bardelli ◽

...

Keyword(s):

Regulatory Element ◽

Hormone Deficiency ◽

Luciferase Reporter ◽

Pituitary Hormone ◽

Mcf7 Cells ◽

Luciferase Reporter Gene ◽

Risk Alleles ◽

Intron 1 ◽

Sporadic Cases ◽

Prop1 Gene

Context: Mutations within the PROP1 gene represent one of the main causes of familial combined pituitary hormone deficiency (CPHD). However, most of the cases are sporadic with an unknown genetic cause. Objective: The aim of this study was the search for low penetrance variations within and around a conserved regulatory element in the intron 1 of PROP1, contributing to a multifactorial form of the disease in sporadic patients. Methods and Patients: A fragment of 570 bp encompassing the conserved region was sequenced in 107 CPHD patients and 294 controls, and an association study was performed with the four identified variants, namely c.109+435G>A (rs73346254), c.109+463C>T (rs4498267), c.109+768C>G (rs4431364), and c.109+915_917ins/delTAG (rs148607624). The functional role of the associated polymorphisms was evaluated by luciferase reporter gene expression analyses and EMSA. Results: A statistically significant increased frequency was observed in the patients for rs73346254A (P = 5 × 10−4) and rs148607624delTAG (P = 0.01) alleles. Among all the possible allele combinations, only the haplotype bearing both risk alleles showed a significantly higher frequency in the patients vs. controls (P = 4.7 × 10−4) and conferred a carrier risk of 4.19 (P = 1.2 × 10−4). This haplotype determined a significant decrease of the luciferase activity in comparison with a basal promoter and the other allelic combinations in GH4C and MCF7 cells (P = 4.6 × 10−6; P = 5.5 × 10−4, respectively). The EMSA showed a differential affinity for nuclear proteins for the alternative alleles of the two associated variations. Conclusions: Variations with a functional significance conferring susceptibility to CPHD have been identified in the PROP1 gene, indicating a multifactorial origin of this disorder in sporadic cases.

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PROP1 Gene Screening in Patients with Multiple Pituitary Hormone Deficiency Reveals Two Sites of Hypermutability and a High Incidence of Corticotroph Deficiency

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.9.7811 ◽

2001 ◽

Vol 86 (9) ◽

pp. 4529-4535 ◽

Cited By ~ 51

Author(s):

S. Vallette-Kasic ◽

A. Barlier ◽

C. Teinturier ◽

A. Diaz ◽

M. Manavela ◽

...

Keyword(s):

Point Mutations ◽

Hormone Deficiency ◽

Heterozygous Mutation ◽

Pituitary Hormone ◽

Gene Encoding ◽

Exon 2 ◽

High Incidence ◽

Prop1 Gene ◽

Gene Alterations

Alterations of the gene encoding the pituitary transcription factor PROP1 were associated with congenital forms of multiple pituitary hormone deficiencies in several families. Among 23 patients with multiple pituitary hormone deficiencies screened for a PROP1 gene abnormality, nine belonging to eight unrelated families had homozygous PROP1 gene defects. All mutations were located in exon 2 and affected only two different sites: a homozygous AG deletion at codons 99/100/101 (n = 5); homozygous point mutations affecting codon 73: R73C (n = 2) or R73H (n = 1), and a R73C/R99X double-heterozygous mutation (n= 1). R73H and R99X were never described. All patients were born to unaffected parents, and consanguinity was documented in two patients. They had complete GH, LH-FSH, and TSH deficiencies and normal basal levels of PRL. Delayed ACTH deficiency was diagnosed in four of nine patients. At magnetic resonance imaging the anterior pituitary was hypoplastic in seven patients and hyperplastic in two. This study found two novel mutations (R73H and R99X) and underlines the high incidence of PROP1 gene alterations in patients with multiple pituitary hormone deficiencies. A corticotroph deficiency was frequently observed in association with GH, TSH, and gonadotropin deficiencies and should be carefully sought during follow-up.

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Late onset adrenocorticotrope deficiency in combined pituitary hormone deficiency caused by a mutation of the PROP1 gene

Endocrine Abstracts ◽

10.1530/endoabs.56.p721 ◽

2018 ◽

Author(s):

Silvia Paredes ◽

Olinda Marques ◽

Marta Alves

Keyword(s):

Late Onset ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Pituitary Hormone Deficiency ◽

Combined Pituitary Hormone Deficiency ◽

Prop1 Gene

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A mutation of the β-domain in POU1F1 causes pituitary deficiency due to dominant PIT-1β expression

Acta Endocrinologica ◽

10.1530/eje-20-1313 ◽

2021 ◽

Author(s):

Shigeru Suzuki ◽

Kumihiro Matsuo ◽

Yoshiya Ito ◽

Atsushi Kobayashi ◽

Takahide Kokumai ◽

...

Keyword(s):

Hormone Deficiency ◽

Luciferase Reporter ◽

Heterozygous Mutation ◽

Pituitary Hormone ◽

Pituitary Cells ◽

Transactivation Domain ◽

Exon 2 ◽

Pituitary Development ◽

Long Term Follow Up ◽

Alternatively Spliced

Background: POU1F1 encodes both PIT-1α, which plays pivotal roles in pituitary development and GH, PRL and TSHB expression, and the alternatively spliced isoform PIT-1β, which contains an insertion of 26-amino acids (β-domain) in the transactivation domain of PIT-1α due to the use of an alternative splice acceptor at the end of the first intron. PIT-1β is expressed at much lower levels than PIT-1α and represses endogenous PIT-1α transcriptional activity. Although POU1F1 mutations lead to combined pituitary hormone deficiency (CPHD), no patients with β-domain mutations have been reported. Results: Here, we report that a three-generation family exhibited different degrees of CPHD, including growth hormone deficiency with intrafamilial variability of prolactin/TSH insufficiency and unexpected prolactinoma occurrence. The CPHD was due to a novel POU1F1 heterozygous variant (c.143-69T>G) in intron 1 of PIT-1α (RefSeq number NM_000306) or as c.152T>G (p.Ile51Ser) in exon 2 of PIT-1β (NM_001122757). Gene splicing experiments showed that this mutation yielded the PIT-1β transcript without other transcripts. Lymphocyte PIT-1β mRNA expression was significantly higher in the patients with the heterozygous mutation than a control. A luciferase reporter assay revealed that the PIT-1β-Ile51Ser mutant repressed PIT-1α and abolished transactivation capacity for the rat prolactin promoter in GH3 pituitary cells. Conclusions: We describe, for the first time, that PIT-1β mutation can cause CPHD through a novel genetic mechanism, such as PIT-1β overexpression, and that POU1F1 mutation might be associated with a prolactinoma. Analysis of new patients and long-term follow-up are needed to clarify the characteristics of PIT-1β mutations.

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A novel PROP1 gene mutation (157delA) in Japanese siblings with combined anterior pituitary hormone deficiency

Clinical Endocrinology ◽

10.1111/j.1365-2265.2004.02147.x ◽

2004 ◽

Vol 61 (5) ◽

pp. 635-640 ◽

Cited By ~ 16

Author(s):

Ke-ita Tatsumi ◽

Kiyoshi Kikuchi ◽

Kumi Tsumura ◽

Nobuyuki Amino

Keyword(s):

Gene Mutation ◽

Anterior Pituitary ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Pituitary Hormone Deficiency ◽

Anterior Pituitary Hormone ◽

Prop1 Gene

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The c.301_302delAG PROP1 gene mutation in Romanian patients with multiple pituitary hormone deficiency

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2014-0289 ◽

2015 ◽

Vol 28 (9-10) ◽

Cited By ~ 1

Author(s):

Cecilia Lazea ◽

Paula Grigorescu-Sido ◽

Radu Popp ◽

Marie Legendre ◽

Serge Amselem ◽

...

Keyword(s):

High Frequency ◽

Bone Age ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Homozygous State ◽

Pituitary Hormone Deficiency ◽

Homozygous Genotype ◽

Familial Form ◽

History Of ◽

Prop1 Gene

AbstractTo establish the frequency of the c.301_302 delAG mutation of theSomatic assessment, hormonal test, bone age, magnetic resonance imaging of the pituitary gland, and molecular diagnosis were performed in 26 patients with MPHD (7 patients with familial form of MPHD and 19 patients with sporadic form of MPHD).The c.301_302delAG mutation was detected in the homozygous state in 10 patients belonging to 5 unrelated families (7 patients with familial history of MPHD and 3 patients with sporadic form of MPHD). Those 10 patients presented variable pituitary hormone deficiency and pituitary morphology.The c.301_302delAG homozygous genotype had a high frequency of 38% (10/26), reaching 100% (7/7) in group with familial cases of MPHD and 16% (3/19) in group with sporadic forms of MPHD.

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Molecular analysis of the PROP1 and HESX1 genes in patients with septo-optic dysplasia and/or pituitary hormone deficiency

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302010000500009 ◽

2010 ◽

Vol 54 (5) ◽

pp. 482-487 ◽

Cited By ~ 3

Author(s):

Juliana B. Cruz ◽

Vania S. Nunes ◽

Sueli A. Clara ◽

Denise Perone ◽

Peter Kopp ◽

...

Keyword(s):

Gene Mutations ◽

Genetic Alterations ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Pituitary Hormone Deficiency ◽

Exon 1 ◽

Genetic Mechanisms ◽

Direct Sequence Analysis ◽

Prop1 Gene ◽

Pathogenic Process

OBJECTIVE: The present study aimed at evaluating the PROP1 and HESX1 genes in a group of patients with septo-optic dysplasia (SOD) and pituitary hormone deficiency (combined - CPHD; isolated GH deficiency - GHD). Eleven patients with a clinical and biochemical presentation consistent with CPHD, GHD or SOD were evaluated. SUBJECTS AND METHODS: In all patients, the HESX1 gene was analyzed by direct sequence analysis and in cases of CPHD the PROP1 gene was also sequenced. RESULTS: A polymorphism (1772 A > G; N125S) was identified in a patient with SOD. We found three patients carrying the allelic variants 27 T > C; A9A and 59 A > G; N20S in exon 1 of the PROP1 gene. Mutations in the PROP1 and HESX1 genes were not identified in these patients with sporadic GHD, CPHD and SOD. CONCLUSION: Genetic alterations in one or several other genes, or non-genetic mechanisms, must be implicated in the pathogenic process.

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