Familial combined pituitary hormone deficiency due to a novel mutation R99Q in the hot spot region of Prophet of Pit-1 presenting as constitutional growth delay.
Details
Serval ID
serval:BIB_A94D1CCA9C98
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Familial combined pituitary hormone deficiency due to a novel mutation R99Q in the hot spot region of Prophet of Pit-1 presenting as constitutional growth delay.
Journal
The Journal of clinical endocrinology and metabolism
ISSN
0021-972X (Print)
ISSN-L
0021-972X
Publication state
Published
Issued date
01/2003
Peer-reviewed
Oui
Volume
88
Number
1
Pages
38-44
Language
english
Notes
Publication types: Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
Combined pituitary hormone deficiency (CPHD) is characterized by impaired production of GH and one or more of the other anterior pituitary hormones. Prophet of Pit-1 (PROP-1), one of the pituitary specific homeodomain transcription factors, is involved in the differentiation of the anterior pituitary cells (somatotrophs, lactotrophs, thyrotrophs, and gonadotrophs), and PROP-1 gene mutations may interfere with the development of these cells, resulting in CPHD. We performed molecular analyses of the PROP-1 gene in two siblings, born to consanguineous parents, who presented with short stature. The index patient, a boy, was initially diagnosed with constitutional growth delay based on familial short stature, low parental target height, normal GH secretion, and imaging of the pituitary gland. On follow-up, auxological data and pubertal delay prompted a thorough reevaluation, which documented GH, TSH, and gonadotropin deficiencies. Direct sequencing of the PROP-1 gene revealed a novel homozygous transition 296G-->A in exon 2 in the two affected siblings. The mutation substitutes a highly conserved arginine by a glutamine at codon 99 (R99Q) in the second helix of the DNA-binding domain of the PROP-1 protein. Compared with wild-type PROP-1, R99Q displays a significant decrease in DNA binding on a paired box response element (PRDQ9) and trans-activation of a luciferase reporter gene. The findings emphasize the importance of repeated evaluations and illustrate that patients with CPHD associated with PROP-1 mutations present with a phenotypic spectrum, suggesting that the consequences of distinct PROP-1 mutations may be diverse and/or that additional factors, such as modifier genes, may have an impact on their expressivity.
Keywords
Adolescent, Adult, Animals, Base Sequence/genetics, Child, DNA/metabolism, DNA Mutational Analysis, Female, Gene Expression, Growth Disorders/etiology, Homeodomain Proteins/genetics, Homeodomain Proteins/metabolism, Humans, Male, Metabolism, Inborn Errors/complications, Metabolism, Inborn Errors/genetics, Mice, Molecular Sequence Data, Mutation/genetics, Pedigree, Pituitary Hormones/deficiency, Protein Structure, Tertiary/genetics, Transfection
Pubmed
Web of science
Open Access
Yes
Create date
30/12/2020 15:44
Last modification date
31/12/2020 7:26