RESUMO
Distal myopathies represent a heterogeneous group of inherited skeletal muscle disorders. One type of adult-onset, progressive autosomal-dominant distal myopathy, frequently associated with dysphagia and dysphonia (vocal cord and pharyngeal weakness with distal myopathy [VCPDM]), has been mapped to chromosome 5q31 in a North American pedigree. Here, we report the identification of a second large VCPDM family of Bulgarian descent and fine mapping of the critical interval. Sequencing of positional candidate genes revealed precisely the same nonconservative S85C missense mutation affecting an interspecies conserved residue in the MATR3 gene in both families. MATR3 is expressed in skeletal muscle and encodes matrin 3, a component of the nuclear matrix, which is a proteinaceous network that extends throughout the nucleus. Different disease related haplotype signatures in the two families provided evidence that two independent mutational events at the same position in MATR3 cause VCPDM. Our data establish proof of principle that the nuclear matrix is crucial for normal skeletal muscle structure and function and put VCPDM on the growing list of monogenic disorders associated with the nuclear proteome.
Assuntos
Miopatias Distais/genética , Mutação de Sentido Incorreto , Proteínas Associadas à Matriz Nuclear/genética , Proteínas de Ligação a RNA/genética , Adulto , Idade de Início , Sequência de Aminoácidos , Substituição de Aminoácidos , Sequência de Bases , Bulgária , DNA/genética , Transtornos de Deglutição/genética , Transtornos de Deglutição/fisiopatologia , Miopatias Distais/patologia , Miopatias Distais/fisiopatologia , Disfonia/genética , Disfonia/fisiopatologia , Feminino , Genes Dominantes , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Matriz Nuclear/fisiologia , Proteínas Associadas à Matriz Nuclear/fisiologia , Linhagem , Proteínas de Ligação a RNA/fisiologia , Homologia de Sequência de Aminoácidos , SíndromeRESUMO
This case report describes neurogenic unilateral leg edema that was a consequence of chronic regional pain syndrome induced by an S1 radiculopathy.
Assuntos
Deslocamento do Disco Intervertebral , Radiculopatia , Humanos , Perna (Membro) , Músculo Esquelético , Edema/diagnóstico por imagem , Edema/etiologiaRESUMO
Constitutional SMARCB1 mutations at 22q11.23 have been found in â¼50% of familial and <10% of sporadic schwannomatosis cases. We sequenced highly conserved regions along 22q from eight individuals with schwannomatosis whose schwannomas involved somatic loss of one copy of 22q, encompassing SMARCB1 and NF2, with a different somatic mutation of the other NF2 allele in every schwannoma but no mutation of the remaining SMARCB1 allele in blood and tumor samples. LZTR1 germline mutations were identified in seven of the eight cases. LZTR1 sequencing in 12 further cases with the same molecular signature identified 9 additional germline mutations. Loss of heterozygosity with retention of an LZTR1 mutation was present in all 25 schwannomas studied. Mutations segregated with disease in all available affected first-degree relatives, although four asymptomatic parents also carried an LZTR1 mutation. Our findings identify LZTR1 as a gene predisposing to an autosomal dominant inherited disorder of multiple schwannomas in â¼80% of 22q-related schwannomatosis cases lacking mutation in SMARCB1.
Assuntos
Cromossomos Humanos Par 22/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Modelos Moleculares , Neurilemoma/genética , Conformação Proteica , Fatores de Transcrição/genética , Sequência de Bases , Proteínas Cromossômicas não Histona/genética , DNA Complementar/genética , Proteínas de Ligação a DNA/genética , Componentes do Gene , Genes Dominantes/genética , Humanos , Perda de Heterozigosidade , Repetições de Microssatélites/genética , Dados de Sequência Molecular , Neurofibromatose 2/genética , Linhagem , Proteína SMARCB1 , Análise de Sequência de DNA , Fatores de Transcrição/químicaRESUMO
MATR3 is an RNA- and DNA-binding protein that interacts with TDP-43, a disease protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in ALS-affected spinal cords with and without MATR3 mutations. Our data provide more evidence supporting the role of aberrant RNA processing in motor neuron degeneration.