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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
A recurring dominant negative mutation causes autosomal dominant growth hormone deficiency-a clinical research center study
Journal of Clinical Endocrinology and Metabolism, Volume 80, No. 12, Year 1995
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Description
Familial isolated GH deficiency type II (IGHD-II) is an autosomal dominant disorder that has been previously shown in some patients to be caused by heterogeneous GH gene defects that affect GH messenger RNA (mRNA) splicing. We report here our finding of multiple G→A transitions of the first base of the donor splice site of IVS 3 (+ 1G→A) in IGHD II subjects from three nonrelated kindreds from Sweden, North America, and South Africa. This + 1G→A substitution creates an NlaIII site that was used to demonstrate that all affected individuals in all three families were heterozygous for the mutation. To determine the effect of this mutation on GH mRNA processing, HeLa cells were transfected with expression plasmids containing normal or mutant + 1G→A alleles, and complementary DNAs from the resulting GH mRNAs were sequenced. The mutation was found to destroy the GH IVS 3 donor splice site, causing skipping of exon 3 and loss of the codons for amino acids 32-71 of the mature GH peptide from the mutant GH mRNA. Our finding of exon 3 skipping in transcripts of the + 1G→A mutant allele is identical to our previous report of a different sixth base transition (+6T→C) mutation of the IVS 3 donor splice site that also causes IGHD II. Microsatellite analysis of an affected subjects’ DNA from each of the three nonrelated kindreds indicates that the + 1G→A mutation arose independently in each family. Finding that neither grandparent has the mutation in the first family suggests that it arose de novo in that family. Our data indicate that 1) + 1G→A IVS 3 mutations perturb GH mRNA splicing and cause IGHD II; and 2) these mutations can present as de novo GHD cases. © 1995 by The Endocrine Society.
Authors & Co-Authors
Cogan, Joy D.
United States, Nashville
Vanderbilt University School of Medicine
Ramel, Bjorn
Sweden, Lund
Lunds Universitet
Lehto, Markku
Sweden, Lund
Lunds Universitet
Phillips, John Atlas
United States, Nashville
Vanderbilt University School of Medicine
Prince, Melissa A.
United States, Nashville
Vanderbilt University School of Medicine
Blizzard, Robert M.
United States, Charlottesville
University of Virginia School of Medicine
de Ravel, Thomy J.L.
South Africa, Johannesburg
University of the Witwatersrand
Brammert, Margareta
Sweden, Lund
Lunds Universitet
Groop, Leif C.
Sweden, Lund
Lunds Universitet
Statistics
Citations: 98
Authors: 9
Affiliations: 4
Identifiers
Doi:
10.1210/jcem.80.12.8530604
ISSN:
0021972X
e-ISSN:
19457197
Research Areas
Cancer
Genetics And Genomics
Study Locations
South Africa