RESUMO
The most frequent inherited peripheral neuropathy is the peripheral myelin protein 22 (PMP22) gene related disease. Duplication, deletion, and point mutations in that gene are associated with phenotypic variability. Here we report a family carrying a novel mutation in the PMP22 gene (c. 327C>A), which results in a premature stop codon (Cys109stop). The family members who carry this mutation have a Charcot-Marie-Tooth type 1 variable phenotype, ranging from asymptomatic to severely affected. These findings suggest that the fourth transmembrane domain of the PMP22 gene may play an important role, although the intrafamilial clinical variability reinforces the observation that pathogenic mutations are not always phenotype determinant and that other factors (genetic or epigenetic) modulate the severity of the clinical course.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Códon de Terminação/genética , Mutação , Proteínas da Mielina/genética , Fenótipo , Adolescente , Adulto , Idoso , Axônios/patologia , Axônios/ultraestrutura , Biópsia/métodos , Doença de Charcot-Marie-Tooth/fisiopatologia , Cisteína/genética , Análise Mutacional de DNA/métodos , Saúde da Família , Feminino , Humanos , Masculino , Microscopia Eletrônica/métodos , Pessoa de Meia-Idade , Exame Neurológico/métodos , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Nervo Sural/patologia , Nervo Sural/ultraestruturaRESUMO
Duchenne muscular dystrophy (DMD), a severe and lethal condition, is caused by the absence of muscle dystrophin. Therapeutic trials aiming at the amelioration of muscle function have been targeting the production of muscle dystrophin in affected Duchenne patients. However, how much dystrophin is required to rescue the DMD phenotype remains an open question. We have previously identified two exceptional golden retriever muscular dystrophy (GRMD) dogs with a milder course despite the total absence of muscle dystrophin. Here we report two unusual patients carrying nonsense mutations in the DMD gene and dystrophin deficiency but with an unexpectedly mild phenotype. Three reported polymorphisms, respectively in genes LTBP4, SPP1 and ACTN3 were excluded as possible DMD genetic modifiers in our patients. Finding the mechanisms that protect some rare patients and dogs from the deleterious effect of absent muscle dystrophin is of utmost importance and may lead to new avenues for treatment. Importantly, these observations indicate that it is possible to have a functional large muscle even without dystrophin.