Complete androgen insensitivity caused by a splice donor site mutation in intron 2 of the human androgen receptor gene resulting in an exon 2-lacking transcript with premature stop-codon and reduced expression

A splice donor site mutation in intron 15 of the cardiac troponin T (TnT) gene has been shown to cause familial hypertrophic cardiomyopathy (HCM). In this study, two truncated human cardiac TnTs expected to be produced by this mutation were expressed in Escherichia coli and partially (50–55%) exchanged into rabbit permeabilized cardiac muscle fibers. The fibers into which a short truncated TnT, which lacked the COOH-terminal 21 amino acids because of the replacement of 28 amino acids with 7 novel residues, had been exchanged generated a Ca2+-activated maximum force that was slightly, but statistically significantly, lower than that generated by fibers into which wild-type TnT had been exchanged when troponin I (TnI) was phosphorylated by cAMP-dependent protein kinase. A long truncated TnT simply lacking the COOH-terminal 14 amino acids had no significant effect on the maximum force-generating capability in the fibers with either phosphorylated or dephosphorylated TnI. Both these two truncated TnTs conferred a lower cooperativity and a higher Ca2+ sensitivity on the Ca2+-activated force generation than did wild-type TnT, independent of the phosphorylation of TnI by cAMP-dependent protein kinase. The results demonstrate that the splice donor site mutation in the cardiac TnT gene impairs the regulatory function of the TnT molecule, leading to an increase in the Ca2+ sensitivity, and a decrease in the cooperativity, of cardiac muscle contraction, which might be involved in the pathogenesis of HCM.

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Evolution of the human gastrokine locus and confounding factors regarding the pseudogenicity of GKN3

Physiological Genomics ◽

10.1152/physiolgenomics.00169.2012 ◽

2013 ◽

Vol 45 (15) ◽

pp. 667-683 ◽

Cited By ~ 9

Author(s):

Jessica H. Geahlen ◽

Carlo Lapid ◽

Kaisa Thorell ◽

Igor Nikolskiy ◽

Won Jae Huh ◽

...

Keyword(s):

Selective Sweep ◽

Stop Codon ◽

Genetic Locus ◽

Donor Site ◽

Premature Stop Codon ◽

Population Based ◽

Splice Donor Site ◽

Human Populations ◽

Selective Sweeps ◽

Gastric Mucous

In a screen for genes expressed specifically in gastric mucous neck cells, we identified GKN3, the recently discovered third member of the gastrokine family. We present confirmatory mouse data and novel porcine data showing that mouse GKN3 expression is confined to mucous cells of the corpus neck and antrum base and is prominently expressed in metaplastic lesions. GKN3 was proposed originally to be expressed in some human populations and a pseudogene in others. To investigate that hypothesis, we studied human GKN3 evolution in the context of its paralogous genomic neighbors, GKN1 and GKN2. Haplotype analysis revealed that GKN3 mimics GKN2 in patterns of exonic SNP allocation, whereas GKN1 appeared to be more stringently selected. GKN3 showed signatures of both directional selection and population based selective sweeps in humans. One such selective sweep includes SNP rs10187256, originally identified as an ancestral tryptophan to premature STOP codon mutation. The derived (nonancestral) allele went to fixation in Asia. We show that another SNP, rs75578132, identified 5 bp downstream of rs10187256, exhibits a second selective sweep in almost all Europeans, some Latinos, and some Africans, possibly resulting from a reintroduction of European genes during African colonization. Finally, we identify a mutation that would destroy the splice donor site in the putative exon3-intron3 boundary, which occurs in all human genomes examined to date. Our results highlight a stomach-specific human genetic locus, which has undergone various selective sweeps across European, Asian, and African populations and thus reflects geographic and ethnic patterns in genome evolution.

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Complete Androgen Insensitivity Caused by a New Frameshift Deletion of Two Base Pairs in Exon 1 of the Human Androgen Receptor Gene1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.84.5.5664 ◽

1999 ◽

Vol 84 (5) ◽

pp. 1751-1753 ◽

Cited By ~ 1

Author(s):

Brigitta Thiele ◽

Wolfgang Weidemann ◽

Doris Schnabel ◽

Gabriela Romalo ◽

Hans-Udo Schweikert ◽

...

Keyword(s):

Androgen Receptor ◽

Stop Codon ◽

Novel Mutation ◽

Reductase Activity ◽

Receptor Gene ◽

Premature Stop Codon ◽

Androgen Receptor Gene ◽

Coding Region ◽

Androgen Insensitivity ◽

Exon 1

We describe a novel mutation in exon 1 of the androgen receptor gene in a patient with complete androgen insensitivity (CAIS). Endocrine findings were typical for androgen insensitivity (testosterone serum levels in the upper limit of normal males and increased LH serum concentrations). Biochemical investigations in cultured genital skin fibroblasts of the patient showed a normal 5α-reductase activity but a complete absence of androgen binding. Western blot analysis revealed no detectable protein product. Sequence analysis of the entire coding region of the androgen receptor gene resulted in the identification of a 2-bp deletion in codon 472, causing frameshift and introduction of a premature stop codon 27 codons downstream of the mutation.

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