Assuntos
Glucoquinase/genética , Hiperglicemia/enzimologia , Hiperglicemia/genética , Mutação , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Etnicidade , Jejum , Feminino , Humanos , Células Secretoras de Insulina/fisiologia , Masculino , Pessoa de Meia-IdadeRESUMO
We performed a prospective genotype-phenotype study using molecular screening and clinical assessment to compare the severity of disease and the risk of sarcoma in 172 individuals (78 families) with hereditary multiple exostoses. We calculated the severity of disease including stature, number of exostoses, number of surgical procedures that were necessary, deformity and functional parameters and used molecular techniques to identify the genetic mutations in affected individuals. Each arm of the genotype-phenotype study was blind to the outcome of the other. Mutations EXT1 and EXT2 were almost equally common, and were identified in 83% of individuals. Non-parametric statistical tests were used. There was a wide variation in the severity of disease. Children under ten years of age had fewer exostoses, consistent with the known age-related penetrance of this condition. The severity of the disease did not differ significantly with gender and was very variable within any given family. The sites of mutation affected the severity of disease with patients with EXT1 mutations having a significantly worse condition than those with EXT2 mutations in three of five parameters of severity (stature, deformity and functional parameters). A single sarcoma developed in an EXT2 mutation carrier, compared with seven in EXT1 mutation carriers. There was no evidence that sarcomas arose more commonly in families in whom the disease was more severe. The sarcoma risk in EXT1 carriers is similar to the risk of breast cancer in an older population subjected to breast-screening, suggesting that a role for regular screening in patients with hereditary multiple exostoses is justifiable.
Assuntos
Neoplasias Ósseas/genética , Condrossarcoma/genética , Exostose Múltipla Hereditária/genética , Lesões Pré-Cancerosas/genética , Adolescente , Adulto , Distribuição por Idade , Idoso , Criança , Exostose Múltipla Hereditária/patologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , N-Acetilglucosaminiltransferases/genética , Fenótipo , Lesões Pré-Cancerosas/patologia , Estudos Prospectivos , Índice de Gravidade de DoençaAssuntos
Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Mutação/genética , Adolescente , Adulto , Criança , Cromatografia Líquida de Alta Pressão/métodos , Análise Mutacional de DNA/métodos , Eletroforese em Gel de Poliacrilamida/métodos , Fibrilina-1 , Fibrilinas , Amplificação de Genes/genética , Análise Heteroduplex/métodos , Humanos , Síndrome de Marfan/diagnóstico , Pessoa de Meia-Idade , Conformação de Ácido Nucleico , Desnaturação de Ácido Nucleico/genética , FenótipoRESUMO
Charcot-Marie-Tooth type 4B (CMT4B), an autosomal recessive demyelinating neuropathy characterized by focally folded myelin sheaths in the peripheral nerve, has been associated with mutations in the gene encoding myotubularin-related protein 2, MTMR2, on chromosome 11q22. To investigate whether mutations in MTMR2 may also cause different forms of CMT, we screened 183 unrelated patients with a broad spectrum of CMT and related neuropathies using denaturing high-performance liquid chromatography. We identified four frequent and three rare exonic variants; two of the rare variants were identified in two unrelated patients with congenital hypomyelinating neuropathy and not in the normal controls. Our results suggest that loss-of-function mutations in MTMR2 are preferentially associated with the CMT4B phenotype.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Cromossomos Humanos Par 11 , Mutação , Proteínas Tirosina Fosfatases/genética , Substituição de Aminoácidos , Doença de Charcot-Marie-Tooth/classificação , Cromatografia Líquida de Alta Pressão , Mapeamento Cromossômico , Éxons , Variação Genética , Homozigoto , Humanos , Mutação Puntual , Reação em Cadeia da Polimerase , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Proteínas Tirosina Fosfatases/química , Proteínas Tirosina Fosfatases não ReceptorasRESUMO
EXT1 and EXT2 are two genes responsible for the majority of cases of hereditary multiple exostoses (HME), a dominantly inherited bone disorder. In order to develop an efficient screening strategy for mutations in these genes, we performed two independent blind screens of EXT1 and EXT2 in 34 unrelated patients with HME, using denaturing high-performance liquid chromatography (DHPLC) and fluorescent single-strand conformation polymorphism analysis (F-SSCP). The mutation likely to cause HME was found in 29 (85%) of the 34 probands: in 22 of these (76%), the mutation was in EXT1; seven patients (24%) had EXT2 mutations. Nineteen of these disease mutations have not been previously reported. Of the 42 different amplicon variants identified in total in the cohort, 40 were detected by DHPLC and 39 by F-SSCP. This corresponds to mutation detection efficiencies of 95% and 93% respectively. We have also found that we can confidently distinguish between different sequence variants in the same fragment using F-SSCP but not DHPLC. In light of this, and the similarly high sensitivities of the two techniques, we propose to continue screening with F-SSCP.