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1.
J Med Genet ; 43(1): 28-38, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15944227

RESUMO

BACKGROUND: Segmental duplications flanking the neurofibromatosis type 1 (NF1) gene locus on 17q11 mediate most gene deletions in NF1 patients. However, the large size of the gene and the complexity of the locus architecture pose difficulties in deletion analysis. We report the construction and application of the first NF1 locus specific microarray, covering 2.24 Mb of 17q11, using a non-redundant approach for array design. The average resolution of analysis for the array is approximately 12 kb per measurement point with an increased average resolution of 6.4 kb for the NF1 gene. METHODS: We performed a comprehensive array-CGH analysis of 161 NF1 derived samples and identified heterozygous deletions of various sizes in 39 cases. The typical deletion was identified in 26 cases, whereas 13 samples showed atypical deletion profiles. RESULTS: The size of the atypical deletions, contained within the segment covered by the array, ranged from 6 kb to 1.6 Mb and their breakpoints could be accurately determined. Moreover, 10 atypical deletions were observed to share a common breakpoint either on the proximal or distal end of the deletion. The deletions identified by array-CGH were independently confirmed using multiplex ligation-dependent probe amplification. Bioinformatic analysis of the entire locus identified 33 segmental duplications. CONCLUSIONS: We show that at least one of these segmental duplications, which borders the proximal breakpoint located within the NF1 intron 1 in five atypical deletions, might represent a novel hot spot for deletions. Our array constitutes a novel and reliable tool offering significantly improved diagnostics for this common disorder.


Assuntos
Quebra Cromossômica , Deleção de Genes , Duplicação Gênica , Neurofibromina 1/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 17/genética , Biologia Computacional , Análise Mutacional de DNA , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Reprodutibilidade dos Testes
4.
Genomics ; 61(3): 259-67, 1999 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-10552927

RESUMO

The gene responsible for the human genetic neurodegenerative disorder DFN-1/MTS encodes a small protein known as deafness/dystonia peptide (DDP). It bears a strong resemblance to a recently characterized set of zinc-binding yeast proteins (Tim8p, Tim9p, Tim10p, Tim12p, and Tim13p) that are implicated in the import of a class of transmembrane carrier proteins from the cytoplasm to the mitochondrial inner membrane. We describe here the human complement of DDP/Tim-like proteins and establish the likely orthologous relationships between sequences from human, yeast, and other organisms. We also describe the expression patterns and chromosomal locations of their genes, which are candidate loci for autosomal recessive neurodegenerative disorders.


Assuntos
Proteínas de Transporte/genética , Surdez/genética , Distonia/genética , Mitocôndrias/metabolismo , Proteínas/genética , Sequência de Aminoácidos , Northern Blotting , Proteínas de Transporte/metabolismo , Mapeamento Cromossômico , Cromossomos Artificiais de Levedura , Humanos , Hibridização in Situ Fluorescente , Dados de Sequência Molecular , Filogenia , Proteínas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Alinhamento de Sequência , Análise de Sequência de DNA , Leveduras/genética , Leveduras/metabolismo
5.
Hum Mutat ; 13(2): 124-32, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10094548

RESUMO

Alport syndrome (AS) can be caused by mutations in COL4A5, one of the six type IV collagen genes. For the purposes of confirming diagnoses, carrier screening and correlating genotype to phenotype, we have screened all 51 exons of this gene by SSCP analysis in 153 families with suspected AS. Mutations were identified in 77 families (of which 20 have previously been reported) and are reported with all available clinical information. All types of mutation were found (missense, nonsense, splicing, small and large deletions and insertions), with the commonest type being those affecting glycine residues in the collagen triple helix. Our 50% detection rate is similar to that of other groups and may imply the presence of mutations outside of the COL4A5 coding region or the existence of a second X-linked AS gene.


Assuntos
Colágeno/genética , Mutação/genética , Nefrite Hereditária/genética , Adolescente , Adulto , Processamento Alternativo/genética , Criança , Códon sem Sentido/genética , Feminino , Mutação da Fase de Leitura/genética , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Deleção de Sequência/genética
6.
Genomics ; 55(1): 21-7, 1999 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-9888995

RESUMO

We report the precise mapping and characterization of the genomic structure of the human homolog of the rat gene for the nucleolar protein NAP57, which has been reported to be responsible for X-linked dyskeratosis congenita (DKC). This single-copy gene, now called DKC, is transcribed from a CpG island 60 kb centromeric to the factor VIII gene in distal Xq28 and lies tail to tail with the palmitoylated erythrocyte membrane protein gene, MPP1. DKC comprises 15 exons spanning at least 16 kb and is transcribed into a widely expressed 2.6-kb message. Several functional motifs of DKC are assigned to coding sequences specified by individual exons. Analysis of normal female DNA revealed the presence of two polymorphisms in the DKC exons, while mutation analysis of a DKC patient identified a novel single amino acid missense mutation in exon 4. The latter together with exon 3 contain five of the six missense mutations reported so far in the DKC gene.


Assuntos
Proteínas de Ciclo Celular/genética , Disceratose Congênita/genética , Proteínas Nucleares/genética , Cromossomo X , Sequência de Aminoácidos , Animais , Sequência de Bases , Mapeamento Cromossômico , DNA , Éxons , Feminino , Ligação Genética , Humanos , Masculino , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Polimorfismo Genético , RNA Mensageiro/genética , RNA Mensageiro/isolamento & purificação , Ratos
7.
Am J Hum Genet ; 63(1): 207-17, 1998 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9634530

RESUMO

Pelizaeus-Merzbacher disease (PMD) is an X-linked, dysmyelinating disorder of the CNS. Duplications of the proteolipid protein (PLP) gene have been found in a proportion of patients, suggesting that, in addition to coding-region or splice-site mutations, overdosage of the gene can cause PMD. We show that the duplication can be detected by interphase FISH, using a PLP probe in five patients and their four asymptomatic carrier mothers. The extent of the duplication was analyzed in each family by interphase FISH, with probes from a 1. 7-Mb region surrounding the PLP gene between markers DXS83 and DXS94. A large duplication >=500 kb was detected, with breakpoints that differed, between families, at the proximal end. Distinct separation of the duplicated PLP signals could be seen only on metaphase chromosomes in one family, providing further evidence that different duplication events are involved. Quantitative fluorescent multiplex PCR was used to confirm the duplication in patients, by the detection of increased copy number of the PLP gene. Multiallelic markers from the duplicated region were analyzed, since the identification of two alleles in an affected boy would indicate a duplication. The majority of boys were homozygous for all four markers, compared with their mothers, who were heterozygous for one to three of the markers. These results suggest that intrachromosomal rearrangements may be a common mechanism by which duplications arise in PMD. One boy was heterozygous for the PLP marker, indicating a duplication and suggesting that interchromosomal rearrangements of maternal origin also can be involved. Since duplications are a major cause of PMD, we propose that interphase FISH is a reliable method for diagnosis and identification of female carriers.


Assuntos
Quebra Cromossômica/genética , Esclerose Cerebral Difusa de Schilder/genética , Família Multigênica/genética , Proteolipídeos/genética , Cromossomo X/genética , Doenças do Sistema Nervoso Central/genética , Sondas de DNA/genética , Marcadores Genéticos/genética , Heterozigoto , Humanos , Hibridização in Situ Fluorescente , Masculino , Reação em Cadeia da Polimerase
8.
Genomics ; 43(2): 171-82, 1997 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-9244434

RESUMO

We have produced a physical map that covers the entirety of Xq21.33 to Xq22.3, from DXS3 to DXS287, approximately 15-17 Mb of the proximal long arm of the human X chromosome. This region has already been shown to contain a number of genes involved in genetic disorders, some of which have yet to be cloned. The physical map consists of a contig of 420 yeast artificial chromosome (YAC) clones ordered with respect to 142 DNA markers, approximately one probe every 110 kb. Forty-three YACs from across the contig have been used to isolate 2019 cosmids that have been mapped into 87 intervals, and 667 of these clones are positive for at least 1 single-copy marker. These YACs and cosmids have been used to confirm data from other published contigs that map to the region. The physical map described here constitutes the first step toward a complete transcriptional map of the region.


Assuntos
Mapeamento Cromossômico , Cromossomos Artificiais de Levedura/genética , Cosmídeos , Cromossomo X/genética , Sondas de DNA , Ligação Genética/genética , Marcadores Genéticos/genética , Humanos
10.
Nat Genet ; 14(2): 177-80, 1996 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8841189

RESUMO

In 1960, progressive sensorineural deafness (McKusick 304,700, DFN-1) was shown to be X-linked based on a description of a large Norwegian pedigree. More recently, it was shown that this original DFN-1 family represented a new type of recessive neurodegenerative syndrome characterized by postlingual progressive sensorineural deafness as the first presenting symptom in early childhood, followed by progressive dystonia, spasticity, dysphagia, mental deterioration, paranoia and cortical blindness. This new disorder, termed Mohr-Tranebjaerg syndrome (referred to here as DFN-1/MTS) was mapped to the Xq21.3-Xq22 region2. Using positional information from a patient with a 21-kb deletion in chromosome Xq22 and sensorineural deafness along with dystonia, we characterized a novel transcript lying within the deletion as a candidate for this complex syndrome. We now report small deletions in this candidate gene in the original DFN-1/MTS family, and in a family with deafness, dystonia and mental deficiency but not blindness. This gene, named DDP (deafness/ dystonia peptide), shows high levels of expression in fetal and adult brain. The DDP protein demonstrates striking similarity to a predicted Schizosaccharomyces pombe protein of no known function. Thus, is it likely that the DDP gene encodes an evolutionarily conserved novel polypeptide necessary for normal human neurological development.


Assuntos
Anormalidades Múltiplas/genética , Surdez/genética , Distonia/genética , Proteínas/genética , Cromossomo X/genética , Adulto , Sequência de Aminoácidos , Sequência de Bases , Cegueira/genética , Análise Mutacional de DNA , Mutação da Fase de Leitura/genética , Ligação Genética , Humanos , Deficiência Intelectual/genética , Íntrons/genética , Masculino , Dados de Sequência Molecular , Linhagem , Regiões Promotoras Genéticas/genética , Pseudogenes/genética , Deleção de Sequência/genética , Homologia de Sequência de Aminoácidos , Síndrome
11.
Genomics ; 37(1): 122-4, 1996 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-8921378

RESUMO

The rat gene Leucine-Rich Primary Response Gene-1 (LRPR1) has been proposed to encode a protein involved in the response of gonadal tissues to follicle-stimulating hormone. We have characterized a human transcript that probably encodes the orthologue of the rat protein, exhibiting 72% identity at the amino acid level. The gene from which the transcript is derived maps to human chromosomal region Xq22 and therefore becomes a potential candidate for human X-linked disorders of gonadal development.


Assuntos
Mapeamento Cromossômico , Proteínas de Ligação a DNA/genética , Hormônio Foliculoestimulante/metabolismo , Zíper de Leucina , Sequência de Aminoácidos , Animais , Humanos , Dados de Sequência Molecular , Ratos , Homologia de Sequência de Aminoácidos
12.
Nat Genet ; 13(2): 223-6, 1996 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8640231

RESUMO

The currently recognised dystrophin protein family comprises the archetype, dystrophin, its close relative, utrophin or dystrophin-related protein (DRP), and a distantly related protein known as the 87K tyrosine kinase substrate. During the course of a phylogenetic study of sequences encoding the characteristic C-terminal domains of dystrophin-related proteins, we identified an unexpected novel class of vertebrate dystrophin-related sequences. We term this class dystrophin-related protein 2 (DRP2), and suggest that utrophin/DRP be renamed DRP1 to simplify future nomenclature. DRP2 is a relatively small protein, encoded in man by a 45 kb gene localized to Xq22. It is expressed principally in the brain and spinal cord, and is similar in overall structure to the Dp116 dystrophin isoform. The discovery of a novel relative of dystrophin substantially broadens the scope for study of this interesting group of proteins and their associated glycoprotein complexes.


Assuntos
Proteínas do Citoesqueleto/química , Proteínas do Citoesqueleto/genética , Distrofina/química , Distrofina/genética , Proteínas de Membrana , Proteínas Musculares , Homologia de Sequência de Aminoácidos , Sequência de Aminoácidos , Animais , Sequência de Bases , Mapeamento Cromossômico , Proteínas do Citoesqueleto/classificação , Cação (Peixe)/genética , Distrofina/biossíntese , Peixes/genética , Humanos , Camundongos , Dados de Sequência Molecular , Filogenia , Análise de Sequência de DNA , Distribuição Tecidual , Utrofina , Cromossomo X
13.
Hum Mol Genet ; 4(4): 693-700, 1995 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-7633420

RESUMO

X-linked agammaglobulinaemia (XLA) is an inherited immunodeficiency resulting from mutations in the gene for a cytoplasmic protein tyrosine kinase (Btk). We have utilised reverse-transcription-based PCR in combination with the chemical cleavage and mismatch technique (CCM) to screen for Btk mutations in 42 unrelated patients having classical XLA or 'leaky' XLA-like phenotypes. A variety of mutations, including point mutations, large deletions and splicing defects were detected using this strategy. In total, 20 mutations were found in these patients. All the mutations were different with the exception of three unrelated patients who all showed the same Arg-->His amino acid substitution (R641H) at a highly-conserved residue in the kinase domain. We have also used structural modelling of the Btk kinase domain to predict how two different amino acid substitution mutations at highly-conserved residues are likely to affect the Btk kinase activity.


Assuntos
Agamaglobulinemia/genética , Ligação Genética , Mutação , Proteínas Tirosina Quinases/genética , Cromossomo X , Tirosina Quinase da Agamaglobulinemia , Aminoácidos/genética , Sequência de Bases , Primers do DNA , Humanos , Masculino , Dados de Sequência Molecular , RNA Mensageiro/genética , Regiões Terminadoras Genéticas
14.
Proc Natl Acad Sci U S A ; 91(26): 12803-7, 1994 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-7809124

RESUMO

X-linked agammaglobulinemia (XLA) is a hereditary defect of B-cell differentiation in man caused by deficiency of Bruton tyrosine kinase (BTK). A three-dimensional model for the BTK kinase domain, based on the core structure of cAMP-dependent protein kinase, was used to interpret the structural basis for disease in eight independent point mutations in patients with XLA. As Arg-525 of BTK has been thought to functionally substitute for a critical lysine residue in protein-serine kinases, the mutation Arg-525-->Gln was studied and found to abrogate the tyrosine kinase activity of BTK. All of the eight mutations (Lys-430-->Glu, Arg-520-->Glu, Arg-525-->Gln, Arg-562-->Pro, Ala-582-->Val, Glu-589-->Gly, Gly-594-->Glu, and Gly-613-->Asp) were located on one face of the BTK kinase domain, indicating structural clustering of functionally important residues.


Assuntos
Agamaglobulinemia/enzimologia , Proteínas Tirosina Quinases/metabolismo , Trifosfato de Adenosina/metabolismo , Tirosina Quinase da Agamaglobulinemia , Sequência de Aminoácidos , Simulação por Computador , Humanos , Magnésio/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Fosforilação , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/química , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Relação Estrutura-Atividade , Cromossomo X
16.
Hum Genet ; 94(1): 77-9, 1994 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-8034298

RESUMO

Mutations within the btk gene have recently been shown to cause X-linked agammaglobulinaemia (XLA). Altered patterns of DNA restriction fragments are seen by Southern blot analysis of DNA from affected patients with deletions in the btk gene. We have identified seven affected families in which altered restriction fragments can be used to diagnose and confirm the carrier status of female relatives of affected boys and in prenatal diagnosis.


Assuntos
Agamaglobulinemia/genética , Deleção de Genes , Triagem de Portadores Genéticos , Ligação Genética , Cromossomo X , Southern Blotting , Feminino , Humanos , Masculino , Linhagem
17.
Genomics ; 21(3): 517-24, 1994 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-7959728

RESUMO

A regional physical and transcription map involving yeast artificial chromosomes (YACs), cosmids, and cDNAs has been constructed for Xq21.3-q22 around the gene BTK (formerly atk or BPK) defective in X-linked agammaglobulinemia (XLA). With a positional cloning strategy employing direct cDNA selection, novel cDNAs were found to cluster in the region of approximately 100 kb flanking the XLA and alpha-galactosidase A loci. While these widely expressed transcripts are in the area known to contain CpG islands, a less evolutionarily conserved gene, located more than 130 kb distal of DXS178, maps to cosmid clones that could not be digested with rare-cutting restriction enzymes. The presence of transcribed sequences flanking the BTK allowed us to investigate their involvement in complex XLA phenotypes. Southern blot analysis using cDNA clones isolated from this region permitted us to exclude a contiguous deletion syndrome as an underlying defect in three patients with XLA and associated growth hormone deficiency. A single XLA patient with torsion dystonia and cosegregating X-linked deafness has been found with a deletion in the 3' part of BTK extending centromerically into the flanking expressed sequence DXS1274E. This suggests a possible involvement of the DXS1274E in this phenotype. The GenBank accession numbers for novel cDNA sequences are as follows: DXS1269E (L20773), DXS1271E (UO1923), DXS1273E (UO1925), and DXS1274E (UO1922).


Assuntos
Cosmídeos/isolamento & purificação , DNA Complementar/isolamento & purificação , Proteínas Tirosina Quinases/genética , Cromossomo X , Tirosina Quinase da Agamaglobulinemia , Agamaglobulinemia/enzimologia , Agamaglobulinemia/genética , Southern Blotting , Mapeamento Cromossômico , Cromossomos Artificiais de Levedura , Clonagem Molecular , Feminino , Biblioteca Gênica , Marcadores Genéticos , Humanos , Cariotipagem , Dados de Sequência Molecular , Mapeamento por Restrição , Transcrição Gênica
18.
Genomics ; 19(1): 42-7, 1994 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-8188239

RESUMO

The Xq22 region of the human X chromosome contains genes for a number of inherited disorders. Sixty-nine yeast artificial chromosome clones have been isolated and assembled into a 6.5-Mb contig that contains 33 DNA markers localized to this region. This contig extends distally from DXS366 to beyond DXS87 and includes the genes involved in X-linked agammaglobulinemia (btk), Fabry disease (GLA), and Pelizaeus-Merzbacher disease (PLP). The order of markers in this contig is consistent with the known genetic and physical mapping information of Xq22. This cloned material provides a source from which to isolate other genes located in this part of the X chromosome.


Assuntos
Cromossomos Artificiais de Levedura , Marcadores Genéticos , Cromossomo X , Adulto , Agamaglobulinemia/genética , Passeio de Cromossomo , Esclerose Cerebral Difusa de Schilder/genética , Doença de Fabry/genética , Biblioteca Gênica , Humanos
19.
Hum Genet ; 92(1): 95-9, 1993 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8103505

RESUMO

X-linked agammaglobulinaemia (XLA) is an inherited disorder characterised by a lack of circulating B-cells and antibodies. While the gene involved in XLA has not yet been identified, the locus for the disorder is tightly linked to the polymorphic marker DXS178, which maps to Xq22. Fabry disease is an X-linked recessive disorder caused by a deficiency in the lysosomal enzyme alpha-galactosidase A. The gene encoding this enzyme has been characterized and also maps to Xq22. Using pulsed field gel electrophoresis we have constructed a long-range restriction map that shows that the alpha-galactosidase A gene (GLA) and DXS178 lie no more than 140 kb apart on a stretch of DNA containing a number of putative CpG islands. We have also isolated yeast artificial chromosome (YAC) clones that confirm this physical linkage. The localisation of DXS178 near the alpha-galactosidase A gene will facilitate carrier detection in Fabry families using restriction fragment length polymorphism (RFLP) analysis. The identification of a number of CpG islands near DXS178 also provides candidate locations for the gene responsible for XLA.


Assuntos
Agamaglobulinemia/genética , Cromossomo X , alfa-Galactosidase/genética , Animais , Sequência de Bases , Linhagem Celular , Mapeamento Cromossômico , Cromossomos Fúngicos , Clonagem Molecular , DNA , Eletroforese em Gel de Campo Pulsado , Doença de Fabry/genética , Feminino , Biblioteca Gênica , Marcadores Genéticos , Genoma Humano , Humanos , Células Híbridas , Masculino , Dados de Sequência Molecular , Polimorfismo de Fragmento de Restrição
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