Complete testicular feminization caused by an amino-terminal truncation of the androgen receptor with downstream initiation.

Zoppi, S.; Wilson, Carol M.; Harbison, Madeleine D.; Griffin, James E.; Wilson, Jean D.; McPhaul, Michael J.; Marcelli, Marco

doi:10.1172/jci116269

Cited by 87 publications

(38 citation statements)

References 27 publications

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“…Types of amino-terminal domain mutations include premature stop codons (28), frameshifts (29, 30) and a single missense mutation, (31) and expansions of the homopolymeric CAG trinucleotide repeat (32). In the present report, we characterize a novel molecular mechanism for AIS resulting from a G to A substitution in codon 2 adjacent to the translation initiation codon in the amino-terminal domain of the AR in three related individuals with partial AIS.…”

Section: Discussionmentioning

confidence: 81%

A novel missense mutation in the amino-terminal domain of the human androgen receptor gene in a family with partial androgen insensitivity syndrome causes reduced efficiency of protein translation.

Choong

Quigley

French³

et al. 1996

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 81%

A novel missense mutation in the amino-terminal domain of the human androgen receptor gene in a family with partial androgen insensitivity syndrome causes reduced efficiency of protein translation.

Choong

Quigley

French³

et al. 1996

J. Clin. Invest.

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“…This AR doublet is also found in the human prostate tumor cell line LNCaP and is believed to reflect posttranslational phosphorylation of the 110-kDa AR gene product (11). In a previous study (12), we identified a mutation in the N-terminal region of the AR gene carried by a 46,XY phenotypic female (R776) with the syndrome of complete testicular feminization; this mutation introduces a premature termination codon in place of the normal AR codon for amino acid 60 (Fig. 1B).…”

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confidence: 66%

A and B forms of the androgen receptor are present inhuman genital skin fibroblasts.

Wilson

McPhaul

1994

Proc. Natl. Acad. Sci. U.S.A.

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136

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Two forms of the androgen receptor (AR) protein (apparent molecular masses, are present in human genital skin fibroblasts. The 87-kDa isoform (AR-A) contains an intact C terminus but lacks the normal N terminus found in the 11O-kDa isoform (AR-B).AR-A is the same size as the mutant form of AR produced in fibroblasts from an androgen-resistant individual (R776) by initiation of AR synthesis at the internal Met-188 residue of AR-B. The ratio of AR-B to AR-A in fibroblasts derived from normal individuals is =10:1. The AR isoforms detected in these experiments resemble the A and B f9rms of the human progesterone receptor, which also are encpded by a single gene and differ by the absence or presence of an N-te lsegment. The A and B forms of the human progesterone receptor differ in their ability to activate target genes and are regulated differently in various types ofcells. The identification ofsimilar forms of human AR raises the possibility that AR-A and AR-B also subserve different functions.

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“…Initiator codon mutations are uncommon, but typically they are associated with null alleles as no functional protein is produced [44][45][46][47]. However, in a few cases, translation of the mutant allele initiates from a downstream methionine or other amino acid, producing a truncated protein that retains partial or full function [48][49][50]. The in vitro transcription/translation experiments indicated that the wild-type ankyrin cDNA initiates only from the known initiator methionine and that the ankyrin New Haven cDNA does not utilize an alternate translation initiation codon.…”

Section: Discussionmentioning

confidence: 99%

Ankyrin‐linked hereditary spherocytosis in an African–American kindred

et al. 2008

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Mutations of ankyrin-1 are the most frequent cause of the inherited hemolytic anemia, hereditary spherocytosis (HS), in people of European ancestry. Ankyrin-1, which provides the primary linkage between the erythrocyte membrane skeleton and the plasma membrane, has numerous isoforms generated by alternative splicing, alternate polyadenylation, use of tissue-specific promoters, and alternate NH 2 or COOH-termini. Mutation detection in erythrocyte membrane protein genes, including ankyrin, has been a challenge, primarily due to the large size of these genes, and the apparent frequent occurrence of HS-associated null alleles. Using denaturing high-performance liquid chromatography (DHPLC), we screened the ankyrin gene of the proband of a large, three generation African-American kindred with ankyrin-deficient HS. DHPLC yielded an abnormal chromatogram for exon 1. Examination of the corresponding exon 1 sequence in genomic DNA from the proband revealed heterozygosity for a mutation of the initiator methionine (ATG to ATA Met 1 Ile). Coupled in vitro transcription/translation studies with rabbit reticulocyte lysates demonstrated that the wild-type ankyrin erythroid cDNA initiates only from the known initiator methionine, indicating that the use of alternate initiator methionine is not a mechanism of isoform diversity in erythroid cells. The mutant ankyrin allele, unlike some initiator methionine mutations that utilize downstream codons for translation initiation, was associated with a null allele. This is the first report describing ankyrin-linked HS in an African-American kindred. Am. J. Hematol. 83:789-794, 2008. V

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Complete testicular feminization caused by an amino-terminal truncation of the androgen receptor with downstream initiation.

Abstract: We have characterized the molecular defect causing androgen resistance in two 46

Cited by 87 publications

References 27 publications

A novel missense mutation in the amino-terminal domain of the human androgen receptor gene in a family with partial androgen insensitivity syndrome causes reduced efficiency of protein translation.

A novel missense mutation in the amino-terminal domain of the human androgen receptor gene in a family with partial androgen insensitivity syndrome causes reduced efficiency of protein translation.

A and B forms of the androgen receptor are present inhuman genital skin fibroblasts.

Ankyrin‐linked hereditary spherocytosis in an African–American kindred

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