RESUMO
KIF1A is a neuron-specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.
Assuntos
Transtornos Cognitivos/genética , Cinesinas/química , Cinesinas/genética , Doenças do Sistema Nervoso/genética , Paraparesia Espástica/genética , Adolescente , Adulto , Criança , Pré-Escolar , Transtornos Cognitivos/patologia , Epilepsia/genética , Epilepsia/patologia , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Neuropatias Hereditárias Sensoriais e Autônomas/patologia , Humanos , Masculino , Modelos Moleculares , Mutação de Sentido Incorreto , Doenças do Sistema Nervoso/patologia , Paraparesia Espástica/patologia , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/patologia , Estrutura Terciária de Proteína , Adulto JovemRESUMO
A 5-year-old girl presented with increasing erythroderma since one day in combination with impetigo vulgaris. As exfoliative lesions and bullae developed within hours, the patient was diagnosed with staphylococcal scalded skin syndrome. She was successfully treated with flucloxacillin.