Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The myotubularin-related 1 (MTMR1) gene belongs to a highly conserved family of eucaryotic phosphatases, with at least 11 members in humans. The founder member of this gene family, MTM1, is mutated in X-linked myotubular myopathy, a severe congenital disorder that affects skeletal muscle, and codes for myotubularin, a specific phosphatidylinositol 3-phosphate [PI(3)P] phosphatase. MTM1 and MTMR1 are adjacent on the X chromosome, and the corresponding proteins share 59% sequence identity. In the present study, we investigated the putative role of MTMR1 in myogenesis by analysing its expression pattern in muscle cells during differentiation and in skeletal muscle throughout development. We have identified three novel coding exons in the MTMR1 intron 2 that are conserved between mouse and human, are alternatively spliced, and give rise to six mRNA isoforms. One of the transcripts is muscle-specific and is induced during myogenesis both in vitro and in vivo, and represents the major isoform in adult skeletal muscle. We show that the two main MTMR1 protein muscular isoforms, like myotubularin, efficiently dephosphorylate PI(3)P in vitro. We have also analysed whether MTMR1 alternative splicing is affected in skeletal muscle cells derived from patients with congenital myotonic dystrophy (cDM1), in which mRNA splicing disturbances of specific genes are thought to constitute an important pathogenic mechanism. We found a striking reduction in the level of the muscle-specific isoform and the appearance of an abnormal MTMR1 transcript in differentiated cDM1 muscle cells in culture and in skeletal muscle from cDM1 patients. Our results suggest that MTMR1 plays a role in muscle formation and represents a novel target for abnormal mRNA splicing in myotonic dystrophy.
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PMID:Muscle-specific alternative splicing of myotubularin-related 1 gene is impaired in DM1 muscle cells. 1221 58

X-linked dystonia parkinsonism (XDP) is an X-linked recessive adult onset movement disorder characterized by both dystonia and parkinsonism. We report delineation of the disease gene within a 300-kb interval of Xq13.1 by allelic association. Sequencing of this region in a patient revealed five disease-specific single-nucleotide changes (here referred to as DSC) and a 48-bp deletion unique to XDP. One of the DSCs is located within an exon of a not previously described multiple transcript system that is composed of at least 16 exons. There is a minimum of three different transcription start sites that encode four different transcripts. Two of these transcripts include distal portions of the TAF1 gene (TATA-box binding protein-associated factor 1) and are alternatively spliced. Three exons overlap with ING2 (a putative tumor suppressor) and with a homologue of CIS4 (cytokine-inducible SH2 protein 4), both of which are encoded by the opposite strand. Although all DSCs are located within this multiple transcript system, only DSC3 lies within an exon. This exon is used by all alternative transcripts making a pathogenic role of DSC3 in XDP likely. The multiple transcript system is therefore referred to as DYT3 (disease locus in XDP).
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PMID:Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism. 1292 96

The orphan nuclear receptor DAX1 (dosage-sensitive sex reversal-AHC critical region on the X chromosome gene 1), encoded by the NR0B1 gene, plays important roles in the development of the hypothalamic-pituitary-adrenal/gonadal (HPAG) axis as well as in sex determination. Mutations in NR0B1 cause the X-linked cytomegalic form of adrenal hypoplasia congenita (AHC), and associated hypogonadotropic hypogonadism (HH). Over-expression of NR0B1 results in sex reversal in mice and duplication of the 160kb DSS locus in human patients results in a sex-reversed phenotype (XY females). The purpose of these investigations was to determine if alternatively spliced forms of NR0B1 existed. Analysis of expressed sequence tag data predicted a truncated isoform of DAX1. We confirmed the presence of an alternatively spliced form of NR0B1, which we will refer to as NR0B1A, by reverse transcriptase-polymerase chain reaction (RT-PCR), and will refer to the deduced protein isoform as DAX1A. Sequencing of the NR0B1A cDNA revealed slight differences from the recently described splice form, DAX1alpha. NR0B1A is encoded by NR0B1 exon 1 and exon 2A located within the 3385 nt intron between NR0B1 exons 1 and 2. Exon 2A includes 35 nt of coding sequence. NR0B1A encodes a deduced protein sequence, DAX1A, of 400 amino acids compared with 470 amino acids for DAX1. RT-PCR detected expression of NR0B1A in adrenal gland, testis, ovary, and pancreas. The identification of NR0B1A and the deduced DAX1A requires reinterpretation of many previous experiments involving expression and knockout of NR0B1 and DAX1.
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PMID:NR0B1A: an alternatively spliced form of NR0B1. 1558 20

Barth syndrome (MIM 302060) is an X-linked condition that includes dilated cardiomyopathy, neutropenia, failure to thrive, abnormal mitochondria, and 3-methylglutaconic aciduria. The mutated gene, TAZ, first described in 1996, appeared to produce a large set of alternatively spliced mRNAs with initiations of transcription upstream of exons 1 and 3. Since then, disease-causing mutations have been found in all exons including, most recently, a missense mutation in the controversial exon 5. Because of the initially described second initiation of transcription in intron 2, with in-frame initiation of translation in exon 3, we hypothesized that subjects with mutations in exons 1 and 2 would produce more normal "short product" that might attenuate their phenotype. Moreover, it was of interest to determine which splice variants were potentially functional as exon 5 is not present in yeast and rodents, and the variant lacking this exon is the most abundant. Using RT-PCR, we characterized TAZ mRNAs in cultured lymphocytes from nine subjects with Barth syndrome and two healthy controls. The TAZ genes and mRNAs of primates were also included. We found the following: (1) there is only one site for initiation of transcription, and the normal alternatively spliced assortment is limited to full-length, delta5, delta7, delta5delta7; (2) there are two alternative splice sites within introns 1 and 2 that could potentially produce an in-frame product; (3) exon 5 evolved into "exonhood" in the primate lineage after the split between Old World monkeys and hominoid primates; and (4) our results suggest that only two functional protein variants exist in lymphocytes: delta5 and full-length. Although exon 5 does not appear to be required for TAZ function in yeast and monkeys, its evolution to a highly conserved spliced exon in hominoid primates and the recent finding of an exon 5 mutation in a patient with Barth syndrome suggest that the full-length variant is important to TAZ function.
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PMID:Barth syndrome: TAZ gene mutations, mRNAs, and evolution. 1579 38

Utrophin is an autosomal homologue of dystrophin, abnormal expression of which is responsible for X-linked Duchenne and Becker muscular dystrophy. In normal mature muscle utrophin is confined to blood vessels, nerves and myotendinous and neuromuscular junctions. When dystrophin is absent utrophin is abundant on the sarcolemma. This has raised the possibility that up-regulation of utrophin may be of therapeutic benefit. Two full-length transcripts of utrophin, A and B, have been identified, which are regulated by alternatively spliced 5' promoters. In dystrophic mouse muscle, the A isoform is present on the sarcolemma, whereas the B form is confined to blood vessels. We show here using immunohistochemistry and human isoform-specific antibodies that A- and B-utrophin localisation is the same in human muscle. The A isoform is present on the sarcolemma of foetal human muscle fibres, regenerating fibres, fibres deficient in dystrophin and on blood vessels and neuromuscular junctions. B-utrophin is only detected on blood vessels. We also show that muscle adjacent to some soft tissue tumours shows increased sarcolemmal utrophin-A, showing that utrophin and dystrophin can simultaneously localise to the sarcolemma and raising the possibility that factor(s) from the tumour cells or accompanying inflammatory cells may have a role in regulating utrophin.
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PMID:A and B utrophin in human muscle and sarcolemmal A-utrophin associated with tumours. 1619 5

Mutations in the proteolipid protein 1 (PLP1) gene cause the X-linked dysmyelinating diseases Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia 2 (SPG2). We examined the severity of the following mutations that were suspected of affecting levels of PLP1 and DM20 RNA, the alternatively spliced products of PLP1: c.453G>A, c.453G>T, c.453G>C, c.453+2T>C, c.453+4A>G, c.347C>A, and c.453+28_+46del (the old nomenclature did not include the methionine codon: G450A, G450T, G450C, IVS3+2T>C, IVS3+4A>G, C344A, and IVS3+28-+46del). These mutations were evaluated by information theory-based analysis and compared with mRNA expression of the alternatively spliced products. The results are discussed relative to the clinical severity of disease. We conclude that the observed PLP1 and DM20 splicing patterns correlated well with predictions of information theory-based analysis, and that the relative strength of the PLP1 and DM20 donor splice sites plays an important role in PLP1 alternative splicing.
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PMID:Splice-site contribution in alternative splicing of PLP1 and DM20: molecular studies in oligodendrocytes. 1628 54

The mouse retrogene Utp14b is essential for male fertility, and a mutation in its sequence results in the sterile juvenile spermatogonial depletion (jsd) phenotype. It is a retrotransposed copy of the Utp14a gene, which is located on the X chromosome, and is inserted within an intron of the autosomal acyl-CoA synthetase long-chain family member 3 (Acsl3) gene. To elucidate the roles of the Utp14 genes in normal spermatogenic cell development as a basis for understanding the defects that result in the jsd phenotype, we analyzed the various mRNAs produced from the Utp14b retrogene and their expression in different cell types. Two classes of transcripts were identified: variant 1, a transcript driven by the host gene promoter, that is predominantly found in germ cells but is ubiquitously expressed at low levels; and variants 2-5, a group of alternatively spliced transcripts containing some unique untranslated exons that are transcribed from a novel promoter that is germ-cell-specific. Utp14b (predominantly variant 1) is expressed at moderately high levels in pachytene spermatocytes, the developmental stage at which the expression of the X-linked Utp14a is suppressed. The levels of both classes of Utp14b transcripts were highest in round spermatids despite the transcription of Utp14a in these cells. We propose that when Utp14b initially inserted into Acsl3, it utilized the Acsl3 promoter to drive expression in pachytene spermatocytes to compensate for inactivation of Utp14a expression. The novel cell-type-specific promoter for Utp14b likely evolved later, as the protein may have acquired a germ cell-specific function in spermatid development.
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PMID:Utp14b: a unique retrogene within a gene that has acquired multiple promoters and a specific function in spermatogenesis. 1729 84

The p21-activated kinases (PAK1), PAK2, and PAK3 are members of the PAK group I and share high sequence identity and common biochemical properties. PAK3 is specifically implicated in neuronal plasticity and also regulates cell cycle progression, neuronal migration, and apoptosis. Loss of function of PAK3 is responsible for X-linked non-syndromic mental retardation whereas gain of PAK3 function is associated with cancer. To understand the functional specificities of PAK3, we analyzed the structure of PAK3 gene products. We report here the characterization of a new alternatively spliced exon called c located upstream of the previously identified exon b. Exon b is detected in all tetrapods and not in fish, exon c is only present in mammals. Mammalian PAK3 genes encode four splice variants and the corresponding proteins were detected with specific antibodies in brain extracts. All PAK3 transcripts are specifically expressed in brain and in particular in neurons. The presence of the exons b and c renders the kinase constitutively active and decreases interaction with GTPases. The expression of the new splice variants in COS7 cells alters cell morphology and modifies the structure of focal adhesions. We propose that the appearance of new alternatively spliced exons during evolution and the resulting increase of complexity of PAK3 gene products may confer new functions to this kinase and contribute to its specific roles in neuronal signaling.
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PMID:The four mammalian splice variants encoded by the p21-activated kinase 3 gene have different biological properties. 1850 5

In this study, we characterize a recessive X-linked temperature-sensitive mutation of the gene CG32711. The mutation, named wiser ( tsl ) (wings scalloped-eyes rough), was isolated from a dysgenic cross and is due to a natural P element insertion within the 5' regulatory region of the gene. Mutant (wiser ( tsl )) individuals exhibit wing notching, rough eyes, tarsal malformations and reduced life-span. At 29 degrees C they die at larval and late pharate stages or during eclosion. The CG32711 (wiser) gene is mainly expressed in the ventral midline cells, the peripheral neural system, the hemocytes and the tracheal system of embryos. It is also expressed in nurse cells of adult female ovaries. Our results show that the wiser gene is alternatively spliced generating two mRNAs, which share the same open reading frame, while western analysis identified two protein isoforms. Their expression pattern depends on the stage of development and the culture temperature. wiser ( tsl ) and wild-type individuals display different expression patterns of the two isoforms and this difference most probably accounts for the mutant phenotype. Our results indicate that wiser is a vital gene for the development of Drosophila melanogaster which has no orthologs outside the Drosophilidae.
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PMID:Wiser (tsl): a recessive X-linked temperature-sensitive lethal mutation that affects the wings and the eyes in Drosophila melanogaster. 1853 96

Total or partial deficiency of the human lysosomal hydrolase alpha-galactosidase A is responsible for Fabry disease, the X-linked inborn error of glycosphingolipid metabolism. Together with the predominant alpha-galactosidase A gene mRNA product encoding the lysosomal enzyme, a weakly regulated alternatively spliced alpha-galactosidase A transcript is expressed in normal tissues, but its overexpression, due to the intronic g.9331G>A mutation, leads to the cardiac variant. We report the molecular characterization of five Fabry patients including two siblings. Sequencing analysis of the alpha-galactosidase A gene coding region and intron/exon boundaries identified the new c.124A>G (p.M42V) genetic lesion as well as a known deletion in three patients, whereas in the two remaining patients, no mutations were identified. To evaluate possible alpha-galactosidase A gene transcription alterations, both predominant and alternatively spliced mRNAs were quantified by absolute real-time PCR on total RNA preparations from the patients' fibroblasts. An impressive reduction in the predominant alpha-galactosidase A transcript was detected in the last patients (Pt 4 and Pt 5). However, the alternatively spliced mRNA was dramatically overexpressed in one of them, carrying a new intronic lesion (g.9273C>T). These findings strongly suggest a correlation between this new intronic mutation and the unbalanced alpha-galactosidase A mRNAs ratio, which could therefore be responsible for the reduced enzyme activity causing Fabry disease. The real-time assay developed here to investigate the two alpha-galactosidase A mRNAs might play a crucial role in revealing possible genetic lesions and in confirming the pathogenetic mechanisms underlying Fabry disease.
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PMID:Unbalanced GLA mRNAs ratio quantified by real-time PCR in Fabry patients' fibroblasts results in Fabry disease. 1856 Apr 46


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