Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Animal models have proven very useful in furthering insight into a number of muscle diseases. Studies of ethanol-fed rats are being used to understand the pathogenetic mechanisms underlying acute and chronic myopathy induced by ethanol. Several animal species, including mice, dogs, and cats, develop X-linked muscular dystrophies, which have genetic defects identical to those of Duchenne muscular dystrophy. As in the human disease, these animals lack dystrophin. They are being used to investigate the mechanisms by which lack of dystrophin results in weakness and to examine myoblast transfer as a treatment modality. A model of eosinophilia-myalgia syndrome has recently been induced in Lewis rats by the feeding of L-tryptophan samples that were implicated in the clinical syndrome in humans, making possible studies of the pathogenesis of this interesting new entity. A dermatomyositis-like syndrome occurs spontaneously in dogs, and polymyositis-like illnesses can be induced in mice by immunization with muscle or following infection with selected viruses, especially enteroviruses. Study of the latter is helping us understand mechanisms in the etiology and pathogenesis of inflammatory myositis and virus-induced autoimmunity.
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PMID:Animal models of myopathy. 177 47

We have discovered in the X-linked androgen receptor gene a single exonic nucleotide substitution that causes complete androgen insensitivity (resistance) in a sibship with three affected individuals. The mutation, a guanine-to-adenine transition, occurs at nucleotide number 2682 and changes the sense of codon 717 from tryptophan to a translation stop signal. Codon 717 is in exon 4, so the mutation predicts the synthesis of a truncated receptor that lacks most of its androgen-binding domain. The substitution abolishes a recognition sequence for the restriction endonuclease HaeIII. Amplification of exon 4 by the polymerase chain reaction followed by double digestion with HinfI and HaeIII permits facile recognition of hemizygotes and heterozygous carriers of the mutation.
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PMID:An exonic point mutation of the androgen receptor gene in a family with complete androgen insensitivity. 233 2

Ornithine transcarbamylase (ornithine carbamoyltransferase, EC 2.1.3.3) deficiency is an X-linked inborn error of metabolism with considerable phenotypic variability in affected males. Using a combination of the polymerase chain reaction and denaturing gradient gel electrophoresis (DGGE), we defined a mutation in a family in whom affected males have significant residual enzyme activity. A C----T change in the first nucleotide of codon 277 resulted in the substitution of a tryptophan for an arginine at amino acid 245 of the mature protein. This change appears to represent a deleterious mutation rather than a polymorphism on the basis of several factors: the change occurs at a highly conserved arginine residue, significant size and change differences exist between arginine and tryptophan, and this change was not seen on DGGE screening of 26 unrelated individuals representing 43 chromosomes. Diagnosis of an at-risk male newborn in this family was performed using direct mutational analysis. In families with partial enzyme deficiencies in whom biochemical data may be difficult to evaluate, direct detection of mutations at the OTC locus permits definitive diagnosis. This represents the first description of a mutation in late onset OTC deficiency and demonstrates direct mutational analysis by DGGE for prospective diagnosis in a genetic disorder.
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PMID:Use of denaturing gradient gel electrophoresis for detection of mutation and prospective diagnosis in late onset ornithine transcarbamylase deficiency. 234 83

The IL2RG gene encoding the gamma chain of the lymphocyte receptor for IL-2 lies in human Xq13.1 and is mutated in males with X-linked severe combined immunodeficiency (SCID). In a large Canadian pedigree genetic linkage studies demonstrated that the proband's grandmother was the source of an X-linked SCID mutation. However, her T cells did not show the expected skewed X chromosome inactivation pattern of female carriers of SCID, despite her having one affected son and two carrier daughters with skewed X inactivation. Single strand conformation polymorphism analysis of IL2RG in the affected proband was abnormal in exon 5; sequencing revealed a nine nucleotide in-frame duplication insertion. The three duplicated amino acids included the first tryptophan of the "WSXWS" motif found in all members of the cytokine receptor gene superfamily. Mutation detection in the pedigree confirmed that the founder grandmother's somatic cells had only normal IL2RG, and further showed that the SCID-associated X chromosome haplotype was inherited by three daughters, one with a wild type IL2RG gene and two others with the insertional mutation. Female germ line mosaicism is unusual, but its presence in this X-linked SCID family emphasizes the limitations of genetic diagnosis by linkage as compared with direct mutation analysis.
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PMID:Female germ line mosaicism as the origin of a unique IL-2 receptor gamma-chain mutation causing X-linked severe combined immunodeficiency. 786 Jul 24

Ten families with X-linked dominant CMT neuropathy (CMTX1) were screened for point mutations of the connexin32 (Cx32, GJB1) gene. Two families showed missense mutations, respectively an A-->G transition at amino acid 102 (glutamate to glycine) and a C-->T transition at amino acid 142 (arginine to tryptophan). Three families showed nonsense mutations, respectively a C-->T transition at amino acid 22 (arginine to stop) a G-->T transversion at amino acid 186 (glutamate to stop), and a T-->A transversion at amino acid 217 (cysteine to stop). Five CMTX1 neuropathy families showed no evidence of point mutations of the connexin32 coding sequence. These findings suggest that the CMTX1 neuropathy genotype is heterogeneous or the result of promoter mutations, 3'-untranslated region mutations or exon/intron splice site mutations. Four of the reported mutations created or destroyed restriction enzyme sites: a HaeIII restriction enzyme site was destroyed by the mutation at amino acid position 22, a HpaII site was eliminated at amino acid position 142, a Bfal restriction site was created by the mutation at amino acid 186 and a Ddel restriction site was created by the mutation at amino acid 217. These changes allowed us to test family members for the mutations and observe the segregation of the disease with the mutations.
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PMID:Point mutations of the connexin32 (GJB1) gene in X-linked dominant Charcot-Marie-Tooth neuropathy. 800 9

In X-linked nephrogenic diabetes insipidus (NDI) the urine of male patients is not concentrated after the administration of the antidiuretic hormone arginine-vasopressin. This disease is due to mutations in the V2 receptor gene that maps to chromosome region Xq28. In 1969, Bode and Crawford suggested that most NDI patients in North America shared common ancestors of Ulster Scot immigrants who arrived in Halifax in 1761 on the ship Hopewell. A link between this family and a large Utah kindred was also suggested. DNA was obtained from 17 affected male patients from the "Hopewell" kindred and from four additional families from Nova Scotia and New Brunswick who shared the same Xq28 NDI haplotype. The Utah kindred and two families (Q2, Q3) from Quebec were also studied. The "Hopewell" mutation, W71X, is a single base substitution (G-->A) that changes codon 71 from TGG (tryptophan) to TGA (stop). The W71X mutation was found in affected members of the Hopewell and of the four satellite families. The W71X mutation is the cause of X-linked NDI for the largest number of related male patients living in North America. Other families (Utah, Q2 and Q3) that are historically and ethnically unrelated bear other mutations in the V2 receptor gene.
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PMID:X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis. 810 96

Congenital nephrogenic diabetes insipidus (DIR) is a rare X-linked hereditary disorder in which the renal collecting duct is unresponsive to arginine vasopressin; thus, the urine is consistently hypotonic to plasma. Recently, the association between the V2 receptor gene (AVPR2) and DIR has been proven. We have determined the gene sequence of four family members, from three generations, of a large North American family with CNDI who were originally part of the study used to formulate the Hopewell hypothesis. It had been proposed that a single DIR gene defect was introduced to North America by a member of an Ulster Scot kindred arriving on the ship Hopewell in 1761. DNA sequencing of the AVPR2 has identified a single base transversion from G-->A which changes tryptophan 71 to a stop codon in affected patients. This point mutation causes a truncation of the receptor leading to an essentially null allele. These data and other recently described mutations in the AVPR2 in North American pedigrees, descended from Ulster Scot ancestors and other origins, make the assertion of a founder effect proposed in the Hopewell hypothesis invalid.
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PMID:A Null mutation in the vasopressin V2 receptor gene (AVPR2) associated with nephrogenic diabetes insipidus in the Hopewell kindred. 840 2

Properdin deficiency is an inherited X-linked disorder causing increased susceptibility to meningococcal disease. Here, underlying genetic defects in the properdin gene were identified for the first time. Samples from individuals with type I deficiency, defined as complete absence of properdin in serum, and individuals with type II deficiency, characterized by low concentrations of properdin in serum, were analyzed by direct chromosome sequencing of overlapping PCR products. The complete gene, including 10 exons and 9 introns, covering 6460 bases of the region Xp11, was investigated by direct solid-phase sequencing. In the related individuals with type I deficiency a C to T mutation in exon 5 was identified, which gives rise to a stop codon TGA and thus a truncated gene product. In addition, point mutations were found in 4 introns and a silent mutation in exon 10. In the properdin gene from related individuals with type II deficiency two point mutations were found, one in intron 3 and one in exon 4. The latter mutation yields a substitution of arginine to tryptophan, which may affect folding, secretion, and/or turnover of the protein. The genetic and biochemical implications of these mutations are discussed.
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PMID:Sequence-based analysis of properdin deficiency: identification of point mutations in two phenotypic forms of an X-linked immunodeficiency. 853 58

Congenital adrenal hypoplasia, an X-linked disorder, is characterized by primary adrenal insufficiency and frequent association with hypogonadotropic hypogonadism. The X-chromosome gene DAX-1 has been most recently identified and shown to be responsible for this disorder. We analyzed the DAX-1 genes of two unrelated Japanese patients with congenital adrenal hypoplasia and hypogonadotropic hypogonadism by using PCR amplification of genomic DNA and its complete exonic sequencing. In a family containing several affected individuals, the proband male patient had a stop codon (TGA) in place of tryptophan (TGG) at amino acid position 171. As expected, his mother was a heterozygous carrier for the mutation, whereas his father and unaffected brother did not carry this mutation. In another male patient with noncontributory family history, sequencing revealed a 1-bp (T) deletion at amino acid position 280, leading to a frame shift and, subsequently a premature stop codon at amino acid position 371. The presence of this mutation in the patients' genome was further confirmed by digestion of genomic PCR product with MspI created by this mutation. Family studies using MspI digestion of genomic PCR products revealed that neither parent of this individual carried the mutation. These results clearly indicate that congenital adrenal hypoplasia and hypogonadotropic hypogonadism result from not only inherited but also de novo mutation in the DAX-1 gene.
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PMID:New mutations of DAX-1 genes in two Japanese patients with X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism. 863 63

Analysis of the X-linked gene PIG-A from haemopoietic cells of a female PNH patient showed a homozygous C-55-T substitution that caused replacement of arginine with tryptophan at codon 19. Aval restriction analysis of PIG-A cDNA demonstrated that the patient was homozygous for this mutation, whereas her mother was heterozygous and her father was hemizygous. Flow cytometry, however, showed normal expression of glycosyl phosphatidylinositol anchored proteins on blood cells of the patient's mother and father. Therefore the C-55-T mutation is an inherited sequence variant that does not account for the PNH phenotype of this patient.
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PMID:Identification and characterization of an inherited mutation of PIG-A in a patient with paroxysmal nocturnal haemoglobinuria. 865 78


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