Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.108 (TAT)
 2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human PDH complex deficiency is an extremely heterogeneous disease in its presentation and clinical course. In an investigation at the level of the gene into ten cases of PDH complex (E1) deficiency, we found that all had mutations in the coding sequence of the X-linked E1 alpha gene while the E1 beta coding sequence was normal. Six of these patients (three males, three females) had missense mutations resulting in a changed amino acid residue in the E1 alpha subunit at positions amino acid 148 (in two siblings), 170, 202, 234 and 263 of the mature protein. Two of the females had one normal E1 alpha gene and one with a deletion at the sites of tandem repeats of AGTAAGA and TAT respectively. The two remaining females also had one normal E1 alpha gene and one with an insertion. Both insertions, one of 2 bp and one of 4 bp, occurred in DNA hotspots normally associated with deletions. Only two of these ten mutations have been reported in other patients previously. In the five cases (including the two siblings) where parent DNA was available, only in one case could the same mutation be found in the patient as well as the maternal genomic DNA.
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PMID:Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase leading to deficiency of the pyruvate dehydrogenase complex. 850 6

The complete androgen insensitivity syndrome (AIS) is a sub-type of X-linked male pseudohermaphroditism resulting from total dysfunction of the androgen receptor. Affected patients are phenotypically female despite a 46,XY genotype; gonadal tissue displays a classic Sertoli cell-only pattern on microscopic examination. We describe the diagnosis and management of a 19(1/2)-year-old patient who presented for primary amenorrhea and absent cervix, identified incidentally during a routine Pap test. Serum total testosterone was elevated (725 ng/dl) and the karyotype was 46,XY. Molecular investigation for specific gene defect(s) causing disruption and functional incapacity of the androgen receptor was undertaken for the proband and her only sibling. From this we discovered a previously unknown hemizygous mutation (A-->T) in exon 4 of the androgen receptor gene, associated with replacement of asparagine (AAT) with tyrosine (TAT) in the resultant androgen receptor protein [N705Y]. Bidirectional, non-isotopic sequence analysis of exon 4 was next undertaken for the proband's sister who was found to be heterozygous for this mutation. Psychological and genetic counseling was provided to both individuals; the patient underwent an outpatient laparoscopic orchiectomy without complication. She continues to receive oral hormone replacement therapy following an oral contraceptive model. In this report, the clinical approach to AIS is outlined from a reproductive endocrinology perspective with special emphasis on psychological counseling and laboratory methods employed to confirm the diagnosis at the molecular level. We also outline other recently described mutations of the androgen receptor gene (Xq11-12) which have been associated with AIS.
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PMID:Characterization of a novel receptor mutation A-->T at exon 4 in complete androgen insensitivity syndrome and a carrier sibling via bidirectional polymorphism sequence analysis. 1174 94

Fabry disease, an X-linked recessive lysosomal storage disease, results from the deficient activity of the exogalactosidase, alpha-galactosidase A (alpha-Gal A). To date, over 270 disease-causing mutations have been identified; however, no coding sequence variants have been reported. In the course of enzyme diagnostic testing, a normal female control had low plasma and leukocyte alpha-Gal A activities. Sequencing her alpha-Gal A gene revealed the D313Y substitution (GAT to TAT at cDNA nucleotide 937). alpha-Gal A mutation and enzyme analyses of family members revealed X-linked transmission and leukocyte alpha-Gal A enzymatic activities in females, consistent with Lyonization. Since D313Y was reported in a classically affected male who had the double mutation, D313Y and G411D, efforts were undertaken to characterize these lesions. Expression of D313Y, G411D, and the doubly mutated construct, D313Y/G411D, resulted in alpha-Gal A levels of 76, 2.9, and 1.7% of mean expressed wild-type activity, respectively. Biosynthetic studies revealed essentially normal processing of the D313Y subunit, but the absence of the mature subunit encoded by the G411D and D313Y/G411D constructs. Thus, G411D is the disease-causing mutation, while D313Y is the first coding sequence variant identified in the human alpha-Gal A gene.
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PMID:Fabry disease: D313Y is an alpha-galactosidase A sequence variant that causes pseudodeficient activity in plasma. 1468 Sep 77

Gene targeting is a precise manipulation of endogenous gene by introduction of exogenous DNA and has contributed greatly to the elucidation of gene functions. Conventional gene targeting has been achieved through a use of embryonic stem cells. However, such procedure is often long, tedious, and expensive. This study was carried out to develop a simple procedure of gene targeting using E. coli recombinase A (RecA) and modified single-stranded oligonucleotides. The new procedure was attempted to modify X-linked hypoxanthine phosphoribosyltransferase (HPRT) gene in mouse embryos. The single-stranded oligonucleotide to target an exon 3 of HPRT was 74 bases in length including phosphorothioate linkages at each terminus to be resistant against exonucleases when introduced into zygotes. The oligonucleotide sequence was homologous to the target gene except a single nucleotide that induces a mismatch between an introduced oligonucleotide and endogenous HPRT gene. Endogenous repairing of such mismatch would give rise to the conversion of TAT to TAG stop codon thereby losing the function of the target gene. Before an introduction into zygotes, single-stranded oligonucleotides were bound to RecA to enhance the homologous recombination. The RecA-oligonucleotide complex was microinjected into the pronucleus of zygote. Individual microinjected embryos developed to the blastocyst stage were analyzed for the expected nucleotide conversion using polymerase chain reaction (PCR) and subsequent sequencing. The conversion of TAT to TAG stop codon was detected in three embryos among 48 tested blastocysts (6.25% in frequency). The result suggests that the gene targeting was feasible by relatively easier and direct method.
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PMID:Gene targeting in mouse embryos mediated by RecA and modified single-stranded oligonucleotides. 1826 50

Complete androgen insensitivity syndrome is an X-linked inherited disorder caused by mutations in the androgen receptor (AR) gene. Using polymerase chain reaction single-strand DNA conformational polymorphism and DNA sequencing, we identified a novel nonsense mutation in exon 1 of the AR gene in 2 Iranian brothers with complete androgen insensitivity syndrome. Despite a normal 46,XY karyotype, testes, and normal to elevated plasma levels of testosterone, they were born with female external genitalia and phenotype. This new mutation, a T-to-A transversion in exon 1, causes amino acid change of tyrosine (TAT) to ochre stop codon (TAA) at position 514 of the AR polypeptide. The Y514X mutation is located in a region that is normally important for the formation and function of the hormone receptor complex. We conclude that the novel Y514X mutation in the androgen receptor is the cause of complete androgen insensitivity syndrome in this family.
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PMID:Identification of a critical novel mutation in the exon 1 of androgen receptor gene in 2 brothers with complete androgen insensitivity syndrome. 1902 43

Lesch-Nyhan disease (LND) is a severe and incurable X-linked genetic syndrome caused by the deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT), resulting in severe alterations of central nervous system, hyperuricemia and subsequent impaired renal functions. Therapeutic options consist in supportive care and treatments of complications, but the disease remains largely untreatable. Enzyme replacement of the malfunctioning cytosolic protein might represent a possible therapeutic approach for the LND treatment. Protein transduction domains, such as the TAT peptide derived from HIV TAT protein, have been used to transduce macromolecules into cells in vitro and in vivo. The present study was aimed to the generation of TAT peptide fused to human HPRT for cell transduction in enzyme deficient cells. Here we document the construction, expression and delivery of a functional HPRT enzyme into deficient cells by TAT transduction domain and by liposome mediated protein transfer. With this approach we demonstrate the correction of the enzymatic defect in HPRT deficient cells. Our data show for the first time the feasibility of the enzyme replacement therapy for the treatment of LND.
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PMID:HIV-1 TAT-mediated protein transduction of human HPRT into deficient cells. 2412 87