"Hot Spot" in the PROP1 Gene Responsible for Combined Pituitary Hormone Deficiency

1999 ◽  
Vol 84 (5) ◽  
pp. 1645-1650 ◽  
Author(s):  
J. Deladoey
Keyword(s):  
Hot Spot ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Pituitary Hormone Deficiency ◽  
Combined Pituitary Hormone Deficiency ◽  
Prop1 Gene

scholarly journals Novel Mutations within the POU1F1 Gene Associated with Variable Combined Pituitary Hormone Deficiency

2005 ◽  
Vol 90 (8) ◽  
pp. 4762-4770 ◽  
Author(s):  
James P. G. Turton ◽  
Rachel Reynaud ◽  
Ameeta Mehta ◽  
John Torpiano ◽  
Alexandru Saveanu ◽  
...  
Keyword(s):  
Dna Binding ◽  
Mutational Analysis ◽  
Hot Spot ◽  
Dominant Negative ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Novel Mutations ◽  
Pituitary Hormone Deficiency ◽  
Combined Pituitary Hormone Deficiency ◽  
Functional Studies

Context: Mutations within the gene encoding the pituitary-specific transcription factor POU1F1 are associated with combined pituitary hormone deficiency (CPHD). Most of the affected individuals manifest GH, prolactin, and TSH deficiency. Objective: We have now screened 129 individuals with CPHD and isolated GH deficiency for mutations within POU1F1. Results: Causative mutations were identified in 10 of 129 individuals (7.8%). Of these, five patients harbored the dominant negative R271W mutation, which is a well-recognized mutational hot spot. We have also identified a second frequently occurring mutation, E230K, which appears to be common in Maltese patients. Additionally, we describe two novel mutations within POU1F1, an insertion of a single base pair (ins778A) and a missense mutation (R172Q). Functional studies have revealed that POU1F1 (E230K) is associated with a reduction in transactivation, although DNA-binding affinity is similar to the wild-type protein. On the other hand, POU1F1 (R172Q) is associated with a reduction in DNA binding and transactivation, whereas POU1F1 (ins778A) is associated with loss of DNA binding and a reduction in transactivation. Conclusions: Our data suggest that the phenotype associated with POU1F1 mutations may be more variable, with the occasional preservation of TSH secretion. Additionally, our data revealed POU1F1 mutations in three patients who were diagnosed as having ACTH deficiency but who, on further evaluation, were found to have normal cortisol secretion. Hence, elucidation of the genotype led to further evaluation of the phenotype, with the cessation of cortisol replacement that had been commenced unnecessarily. These data reflect the importance of mutational analysis in patients with CPHD.

scholarly journals PROP1 gene analysis in Portuguese patients with combined pituitary hormone deficiency

2006 ◽  
Vol 65 (4) ◽  
pp. 479-485 ◽  
Author(s):  
Manuel C. Lemos ◽  
Leonor Gomes ◽  
Margarida Bastos ◽  
Valeriano Leite ◽  
Edward Limbert ◽  
...  
Keyword(s):  
Gene Analysis ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Pituitary Hormone Deficiency ◽  
Combined Pituitary Hormone Deficiency ◽  
Prop1 Gene

scholarly journals Phenotypic Variability in Familial Combined Pituitary Hormone Deficiency Caused by a PROP1 Gene Mutation Resulting in the Substitution of Arg→Cys at Codon 120 (R120C)1

1998 ◽  
Vol 83 (10) ◽  
pp. 3727-3734 ◽  
Author(s):  
Christa Flück ◽  
Johnny Deladoey ◽  
Kuno Rutishauser ◽  
Andrée Eblé ◽  
ULRICH Marti ◽  
...  
Keyword(s):  
Phenotypic Variability ◽  
Failure To Thrive ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Pituitary Hormone Deficiency ◽  
Combined Pituitary Hormone Deficiency ◽  
Ames Dwarf ◽  
Hypothalamic Pituitary Axis ◽  
Prop1 Gene

As pituitary function depends on the integrity of the hypothalamic-pituitary axis, any defect in the development and organogenesis of this gland may account for a form of combined pituitary hormone deficiency (CPHD). A mutation in a novel, tissue-specific, paired-like homeodomain transcription factor, termed Prophet of Pit-1 (PROP1), has been identified as causing the Ames dwarf (df) mouse phenotype, and thereafter, different PROP1 gene alterations have been found in humans with CPHD. We report on the follow-up of two consanguineous families (n = 12), with five subjects affected with CPHD (three males and two females) caused by the same nucleotide C to T transition, resulting in the substitution of Arg→Cys in PROP1 at codon 120. Importantly, there is a variability of phenotype, even among patients with the same mutation. The age at diagnosis was dependent on the severity of symptoms, ranging from 9 months to 8 yr. Although in one patient TSH deficiency was the first symptom of the disorder, all patients became symptomatic by exhibiting severe growth retardation and failure to thrive, which was mainly caused by GH deficiency (n = 4). The secretion of the pituitary-derived hormones (GH, PRL, TSH, LH, and FSH) declined gradually with age, following a different pattern in each individual; therefore, the deficiencies developed over a variable period of time. All of the subjects entered puberty spontaneously, and the two females also experienced menarche and periods before a replacement therapy was necessary.

scholarly journals Genetic background of inherited multiple pituitary hormone deficiency. Mutations of PROP1 gene in Hungary

2011 ◽  
Vol 152 (6) ◽  
pp. 221-232
Author(s):  
Zita Halász
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Mutational Analysis ◽  
Hot Spot ◽  
Gene Mutations ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Multiple Pituitary Hormone Deficiency ◽  
Pituitary Hormone Deficiency ◽  
Prop1 Gene

In this work I analysed the outcome of growth hormone replacement treatment in patients with inherited form of multiple pituitary hormone deficiency and examined diseased-causing mutations of pituitary transcription factor genes which may underlie this disorder. The results showed that after treatment for a longer than 7-year period with a growth hormone preparation available under well-controlled distribution, the mean height of children with growth hormone deficiency reached the normal national reference range adjusted for age and sex. After establishment of clinical criteria for screening PROP1 gene mutations, I performed mutational analysis of all coding exons of this gene in 35 patients with inherited form of multiple pituitary hormone deficiency. With these studies, diseases-causing PROP1 gene mutations were detected in 15 of the 35 patients (43%). It was also found that more than 80% of mutant alleles were accounted for by those containing the 150delA and 301-302delGA mutations of the PROP1 gene. Importantly, these findings indicated a high relevance of mutational ”hot spots” of the PROP1 gene in Hungarian patients with inherited form of multiple pituitary hormone deficiency and they also offered an opportunity for the development of rational and cost-effective screening strategy. When clinical and hormonal findings of patients with and without PROP1 gene mutations were compared, results showed that growth hormone deficiency was diagnosed at earlier age of life in patients with PROP1 gene mutations, but the severity of growth retardation at the time of diagnosis of growth hormone deficiency or the age of patients at the time of manifestation of other pituitary hormone deficiencies (TSH, LH, FSH and ACTH) were similar in the two groups of patients. In 15 patients inherited form of multiple pituitary hormone deficiency who had no PROP1 gene mutations, exon 6 of the POU1F1 gene containing a mutational ”hot spot” was also examined but no mutations were found. Thus, these results do not support a significant role of the mutational ”hot spot” of the POU1F1 gene in Hungarian patients with inherited form of multiple pituitary hormone deficiency. Finally, I introduced a method for the detection of mutations of the PITX2 gene, a pituitary transcription factor that plays a role not only in pituitary development and differentiation but also in the lateralization of organs. With the use of this method, I performed mutational analysis of all coding exons of this gene in an exceptionally unique patient who had both situs inversus totalis and inherited form of multiple pituitary hormone deficiency, but no mutation was found. Thus, the findings in this patient failed to indicate that mutation of the PITX2 gene is involved in the pathomechanism of situs inversus totalis associated with inherited form of multiple pituitary hormone deficiency. Orv. Hetil., 2011, 152, 221–232.

Sign in / Sign up

Export Citation Format

Share Document