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2.
J Med Genet ; 47(4): 249-56, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19889647

RESUMO

INTRODUCTION: The most common form of axonal Charcot-Marie-Tooth (CMT) disease is type 2A, caused by mutations in the mitochondrial GTPase mitofusin 2 (MFN2). OBJECTIVE: The objective of our study is to establish the incidence of MFN2 mutations in a cohort of Spanish patients with axonal CMT neuropathy. MATERIAL AND METHODS: Eighty-five families with suspected axonal CMT were studied. All MFN2 exons were studied through direct sequencing. A bioenergetics study in fibroblasts was conducted using a skin biopsy taken from a patient with an Arg468His mutation. RESULTS: Twenty-four patients from 14 different families were identified with nine different MFN2 mutations (Arg94Trp, Arg94Gln, Ile203Met, Asn252Lys, Gln276His, Gly296Arg, Met376Val, Arg364Gln and Arg468His). All mutations were found in the heterozygous state and four of these mutations had not been described previously. MFN2 mutations were responsible for CMT2 in 16% +/- 7% of the families studied and in 30.8 +/- 14.2% (12/39) of families with known dominant inheritance. The bioenergetic studies in fibroblasts show typical results of MFN2 patients with a mitochondrial coupling defect (ATP/O) and an increase of the respiration rate linked to complex II. CONCLUSION: It is concluded that mutations in MFN2 are the most frequent cause of CMT2 in this region. The Arg468His mutation was the most prevalent (6/14 families), and our study confirms that it is pathological, presenting as a neuropathy in a mild to moderate degree. This study also demonstrates the value of MFN2 studies in cases of congenital axonal neuropathy, especially in cases of dominant inheritance, severe clinical symptoms or additional symptoms such as optic atrophy.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Mutação , Trifosfato de Adenosina/metabolismo , Células Cultivadas , Doença de Charcot-Marie-Tooth/metabolismo , Mapeamento Cromossômico , Ciclo do Ácido Cítrico , Fenômenos Eletrofisiológicos , Fibroblastos/metabolismo , GTP Fosfo-Hidrolases , Humanos , Mitocôndrias/metabolismo , Fenótipo , Pele , Espanha , Estatísticas não Paramétricas
3.
Neuromuscul Disord ; 18(12): 974-8, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18996695

RESUMO

Mutations in the Mitofusin 2 (MFN2) gene have been related to the axonal type of Charcot-Marie-Tooth type 2 (CMT 2A). We report the first two Spanish families with CMT 2 and mutations in MFN2 gene. Molecular studies of one family with late onset revealed the novel mutation Arg364Gln. The affected family members presented mild clinical and electrophysiological worsening after 14 years of follow-up. The other family presented an early onset and optic atrophy. Molecular studies revealed the Arg94Gln mutation. This is the first report of a family in which this mutation is related to optic atrophy. Molecular analysis aimed at detecting mutations of MFN2 could be extremely useful in mild axonal neuropathies with slow evolution and indispensable in cases of dominant inheritance or optic atrophy. Population studies of mutations in MFN2 should be undertaken to discover the real frequencies in the Mediterranean area.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Mutação , Adulto , Sequência de Aminoácidos , Sequência de Bases , Doença de Charcot-Marie-Tooth/complicações , Doença de Charcot-Marie-Tooth/fisiopatologia , Análise Mutacional de DNA/métodos , Eletrofisiologia , Feminino , GTP Fosfo-Hidrolases , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Atrofia Óptica/etiologia , Atrofia Óptica/patologia , Linhagem , Reação em Cadeia da Polimerase , Homologia de Sequência de Aminoácidos , Espanha , Adulto Jovem
4.
Clin Genet ; 70(6): 516-23, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17100997

RESUMO

From 1995 to 2004, 979 families with hereditary peripheral neuropathy were referred to the Genetic Diagnosis Center. Using single-strand conformation analysis (SSCA), the connexin 32 gene was analysed in all the patients from 498 families with sporadic or dominant inheritance with no male-to-male transmission and absence of the 17p2 duplication or deletion. Affected males had pes cavus, distal leg weakness, muscular distal atrophy, areflexia and distal sensory loss. The 106 families in which SSCA revealed abnormal migration electrophoresis were directly sequenced. We found 34 families (59 patients) with mutations in connexin 32 gene. In electrophysiological studies, 58.8% families presented slow and 14.7% intermediate nerve conduction velocities. Molecular findings revealed that codon 164 (29.4 +/- 15.3%) and the second extracellular (EC2) domain (44.1 +/- 16.6%) were the most frequently affected codon and domain of the connexin 32. Six novel mutations, Leu39fs, Glu47Gly, His153fs, Cys179Tyr, Cys201Phe and Ser211fs, were found in our study.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Conexinas/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação/genética , Fenótipo , Sequência de Aminoácidos , Sequência de Bases , Eletrofisiologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Padrões de Herança , Masculino , Dados de Sequência Molecular , Linhagem , Polimorfismo Conformacional de Fita Simples , Conformação Proteica , Alinhamento de Sequência , Análise de Sequência de DNA , Espanha , Proteína beta-1 de Junções Comunicantes
5.
Hum Mol Genet ; 10(9): 947-52, 2001 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-11309368

RESUMO

Mutations in the connexin 31 (GJB3) gene have been found in subjects with dominant and recessive deafness and in patients with erythrokeratodermia variabilis. We report here a dominant mutation in the GJB3 gene (D66del) in a family affected with peripheral neuropathy and sensorineural hearing impairment. A wide range of disease severity for peripheral neuropathy, from asymptomatic cases to subjects with chronic skin ulcers in their feet and osteomyelitis leading to amputations, was detected in D66del patients. Mild, often asymmetrical, hearing impairment was found in all but one patient with mutation D66del of this family and the same mutation was present in an independent family ascertained because of hearing impairment. We have found mouse connexin 31 (Gjb3) gene expression in the cochlea and in the auditory and sciatic nerves, showing a pattern similar to that of Gjb1 (connexin 32), of which the human ortholog (GJB1) is involved in X-linked peripheral neuropathy. This expression pattern, together with auditory-evoked brainstem anomalous response in D66del patients, indicates that hearing impairment due to GJB3 mutations involves alterations in both the cochlea and the auditory nerve. Peripheral neuropathy is the third phenotypic alteration linked to GJB3 mutations, which enlarges the list of genes that cause this group of heterogeneous disorders.


Assuntos
Nervo Coclear/metabolismo , Conexinas/genética , Perda Auditiva Neurossensorial/genética , Doenças do Sistema Nervoso Periférico/genética , Sistema Nervoso Periférico/metabolismo , Adulto , Animais , Conexinas/biossíntese , Análise Mutacional de DNA , Feminino , Expressão Gênica , Humanos , Hibridização In Situ , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mutação , Linhagem , Nervo Isquiático/patologia
6.
Hum Mutat ; 15(5): 481-2, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10790215

RESUMO

Connexin31 (GJB3) has been associated with hearing impairment and erythrokeratodermia variabilis. We have analyzed this gene in samples from patients with peripheral neuropathies, deafness and controls and have found several single nucleotide polymorphisms (SNPs). In the noncoding exon 1 of GJB3 two small deletions, 581del2 and 632del4 (GenBank accession number AF052692), were found at frequencies of 30% and 14%, respectively. In exon 2 we found two amino acid changes, R32W (1227C-T) and V200I (1731G-A), and three nucleotide variants not affecting the amino acid sequence, 1610G-A, 1700C-T and 1931C-T. Most of these changes were found at similar frequencies in patients with deafness, patients with peripheral neuropathies and control subjects. V200I, 1700C-T and 1610G-A were found associated in three unrelated patients with deafness and in a fourth patient with peripheral neuropathy, but were not detected in control subjects.


Assuntos
Substituição de Aminoácidos/genética , Conexinas/genética , Polimorfismo de Nucleotídeo Único/genética , Éxons/genética , Humanos , Regiões não Traduzidas/genética
7.
Hum Genet ; 104(6): 516-22, 1999 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10453742

RESUMO

Autosomal dominant cerebellar ataxias (ADCA) are a clinically heterogeneous group of neurodegenerative disorders caused by unstable CAG repeat expansions encoding polyglutamine tracts. Five spinocerebellar ataxia genes (SCA1, SCA2, SCA3, SCA6 and SCA7) and another related dominant ataxia gene (DRPLA) have been cloned, allowing the genetic classification of these disorders. We present here the molecular analysis of 87 unrelated familial and 60 sporadic Spanish cases of spinocerebellar ataxia. For ADCA cases 15% were SCA2, 15% SCA3, 6% SCA1, 3% SCA7, 1% SCA6 and 1% DRPLA, an extremely rare mutation in Caucasoid populations. About 58% of ADCA cases remained genetically unclassified. All the SCA1 cases belong to the same geographical area and share a common haplotype for the SCA1 mutation. The expanded alleles ranged from 41 to 59 repeats for SCA1, 35 to 46 [corrected] for SCA2, 67 to 77 for SCA3, and 38 to 113 for SCA7. One SCA6 case had 25 repeats and one DRPLA case had 63 repeats. The highest CAG repeat variation in meiotic transmission of expanded alleles was detected in SCA7, this being of +67 units in one paternal transmission and giving rise to a 113 CAG repeat allele in a patient who died at 3 years of age. Meiotic transmissions have also shown a tendency to more frequent paternal transmission of expanded alleles in SCA1 and maternal in SCA7. All SCA1 and SCA2 expanded alleles analyzed consisted of pure CAG repeats, whereas normal alleles were interrupted by 1-2 CAT trinucleotides in SCA1, except for three alleles of 6, 14 and 21 CAG repeats, and by 1-3 CAA trinucleotides in SCA2. No SCA or DRPLA mutations were detected in the 60 sporadic cases of spinocerebellar ataxia, but one late onset patient was identified as a recessive form due to GAA-repeat expansions in the Friedreich's ataxia gene.


Assuntos
Degenerações Espinocerebelares/etnologia , Degenerações Espinocerebelares/genética , Adulto , Idade de Início , Alelos , Ataxina-1 , Ataxina-3 , Ataxina-7 , Ataxinas , Canais de Cálcio/genética , Pré-Escolar , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Proteínas/genética , Proteínas Repressoras , Espanha , Repetições de Trinucleotídeos
8.
J Med Genet ; 35(2): 99-102, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9507387

RESUMO

In some neurodegenerative diseases, genetic anticipation correlates with expansions of the CAG/CTG repeat sequence above the normal range through the generations of a pedigree. Among these neurodegenerative diseases are late onset autosomal dominant cerebellar ataxias (ADCA). ADCA are genetically heterogeneous disorders with different cloned genes for spinocerebellar ataxia type 1 (SCA1), type 2 (SCA2), type 3 or Machado-Joseph disease (SCA3/MJD), and type 6 (SCA6). Another related dominant ataxia, dentatorubral-pallidoluysian atrophy (DRPLA), also shows CAG/CTG repeat expansions. Genetic anticipation has been reported for all of them except for the recently cloned SCA6 gene. Other, as yet undetected SCA genes may show the same features. We have used the repeat expansion detection (RED) method to detect repeat expansions directly in DNA samples from ADCA patients not resulting from known genes. Our sample consists of 19 affected index cases, corresponding to 52.8% of our ADCA families without CAG/CTG repeat expansions in the SCA1, SCA2, SCA3/MJD, SCA6, or DRPLA genes. Eighty-nine percent of the index cases had expansions of a CAG/CTG sequence greater than 40 repeats by RED, while these were observed in only 26.9% of 78 healthy subjects from the general population (p < 0.0001). The distribution of RED fragments in controls and ADCA patients also shows significant differences with the Mann-Whitney U test (U = 376.5, p = 0.0007). Moreover, there was a significant inverse correlation between the size of expansion and the age of onset (r = -0.54, p = 0.018). These results show CAG/CTG repeat expansions of over 40 repeats in our sample of ADCA families not resulting from known SCA genes.


Assuntos
Ataxia Cerebelar/genética , Sequências Repetitivas de Ácido Nucleico/genética , Adulto , Idade de Início , Ataxia Cerebelar/epidemiologia , Criança , DNA/sangue , DNA/química , DNA Ligases/química , Genes Dominantes , Humanos , Pessoa de Meia-Idade , Hibridização de Ácido Nucleico , Sondas de Oligonucleotídeos/química , Análise de Regressão , Sequências Repetitivas de Ácido Nucleico/fisiologia , Espanha/epidemiologia
9.
Hum Genet ; 101(1): 18-21, 1997 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9385362

RESUMO

Genetic anticipation--increasing severity and a decrease in the age of onset with successive generations of a pedigree--is clearly present in autosomal dominant cerebellar ataxia (ADCA). Anticipation is correlated with expansion of the CAG/CTG repeat sequence to sizes above those in the normal range through the generations of a pedigree. Genetic heterogeneity has been demonstrated for ADCA, with four cloned genes (SCA1, SCA2, SCA3/MJD, and SCA6) and three mapped loci (SCA4, SCA5 and SCA7). Another related dominant ataxia, dentatorubral-pallidoluysian atrophy (DRPLA), presents anticipation with CAG/CTG repeat expansions. We had previously analysed ADCA patients who had not shown repeat expansions in cloned genes for CAG/CTG repeat expansions by the repeat expansion detection method (RED) and had detected expansions of between 48 and 88 units in 17 unrelated familial cases. We present here an analysis of 13 genes and expressed sequence tags (ESTs) containing 10 or more CAG/CTG repeat sequences selected from public databases in the 17 unrelated ADCA patients. Of the 13 selected genes and ESTs, 9 were found to be polymorphic with heterozygosities ranging between 0.09 and 0.80 and 2 to 17 alleles. In ADCA patients none of the loci showed expansions above the normal range of the CAG/CTG repeat sequences, excluding them as the mutation causing ADCA.


Assuntos
Ataxia Cerebelar/genética , Repetições de Trinucleotídeos , Sequência de Bases , Análise Mutacional de DNA , Primers do DNA/genética , Feminino , Expressão Gênica , Genes Dominantes , Humanos , Masculino , Repetições Minissatélites , Reação em Cadeia da Polimerase , Polimorfismo Genético
10.
Transpl Int ; 8(6): 488-91, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-8579742

RESUMO

We describe the development of a lymphoma in a liver allograft shortly after orthotopic liver transplantation. Aspiration and core biopsies of the nodule were persistently negative so that a diagnosis could not be made until the patient underwent retransplantation, when examination of the liver resection specimen revealed a B-cell lymphoma. Using a rapid technique based on the polymerase chain reaction, we were able to demonstrate that the tumor was of donor origin.


Assuntos
DNA de Neoplasias/análise , Neoplasias Hepáticas/etiologia , Transplante de Fígado/efeitos adversos , Linfoma de Células B/etiologia , Sequência de Bases , Humanos , Neoplasias Hepáticas/diagnóstico , Linfoma de Células B/diagnóstico , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Transplante Homólogo
12.
Hum Mutat ; 3(4): 365-72, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-8081390

RESUMO

In the analysis of 40 CEPH families, under the EUROGEM project, with a total of 29 microsatellites (26 CA-repeats, a TCTA-repeat within the vWFII-3 gene, a TTA-repeat within the PLA-2 gene, and an AAAT-repeat intragenic to the NF1 gene) from human chromosomes 12, 17, and 21, we have detected 21 cases of abnormal segregation of alleles in 16 pedigrees for a total of 14 markers (48%). In 11 cases, the abnormal transmissions were of somatic origin, 10 of which (91%) occurred in the lymphoblastoid cell lines. In 9 other cases, it was not possible to determine if the origin of the new alleles was somatic or germline, and in one case hemizygosity in several family members was observed, so its origin was germline. The 20 new mutations detected in the 22,852 meioses analysed represent a mutation frequency of 8.7 x 10(-4) per locus per allele. The germline mutation rate could be as high as 3.9 x 10(-4) per locus per gamete (from 0 to 3.9 x 10(-4)), but the rate of somatic mutations detected in the study was much higher (4.8 x 10(-4) to 8.7 x 10(-4) per locus per allele). Individual mutation rates ranged from 0 to 3.8 x 10(-3). Among the markers analysed, all three that were tri- or tetranucleotide repeats showed one or two new alleles, compared to only 10 of the 26 (38%) CA-repeats showing mutations. Three CEPH families (102, 45 and 1333) each had several mutational events, and one individual (10210) had somatic mutations for two microsatellites from different chromosomes.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Alelos , DNA Satélite/genética , Marcadores Genéticos , Mutação , Sequências Repetitivas de Ácido Nucleico , Adulto , Linhagem Celular , Criança , Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 17 , Cromossomos Humanos Par 21 , Análise Mutacional de DNA , Bases de Dados Factuais , Pai , Feminino , Frequência do Gene , Genes da Neurofibromatose 1/genética , Mutação em Linhagem Germinativa , Humanos , Linfócitos , Masculino , Epidemiologia Molecular , Mães , Pâncreas/enzimologia , Linhagem , Fosfolipases A/genética , Reação em Cadeia da Polimerase , Polimorfismo Genético , Fator de von Willebrand/genética
13.
Int J Legal Med ; 105(5): 271-7, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8471544

RESUMO

We have used PCR amplification to analyse the allele frequency, distribution and heterozygosity of 5 microsatellite markers (D1S117, D6S89, D11S35, APOC2, and D21S168), in a sample of 100 unrelated Spanish individuals. The loci tested exhibit wide allelic variability having 7-17 alleles, PIC (polymorphic information content) between 0.79 and 0.86, and heterozygosity between 0.81 and 0.86. D1S117 and D21S168 have unimodal distribution, APOC2 has 4 common alleles which account for 71% of the total variation, D11S35 has a bimodal distribution and D6S89 is trimodal. The allelic distribution observed for each locus is in agreement with slippage and mispairing as the main mechanisms involved in the evolution of microsatellite alleles. Multiplex amplification of loci D6S89 and APOC2 was possible due to their non-overlapping allele sizes. The rapidity with which microsatellites can be analysed, and the accurate determination of alleles, make these markers very powerful tools for genetic typing. The information obtained for loci D1S117, D6S89, D11S35, APOC2, and D21S168, provides a basis for their use for DNA typing and paternity analysis in the Spanish population.


Assuntos
DNA Satélite/genética , Marcadores Genéticos/genética , Variação Genética , Genética Populacional , Alelos , Frequência do Gene/genética , Triagem de Portadores Genéticos , Humanos , Paternidade , Reação em Cadeia da Polimerase , Polimorfismo Genético/genética , Sequências Repetitivas de Ácido Nucleico/genética
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