RESUMEN
A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal-dominant trait, which could not be ascribed to any known mutation. DNA from three affected members was subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically matched controls. Subsequent genotyping was performed in a multi-ethnic case-control series consisting of 2928 patients and 2676 control subjects from Canada, Norway, Taiwan, Tunisia, and the USA. A novel mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13 p.Asn855Ser) was found to segregate with disease. Screening of cases and controls identified four additional patients with the mutation, of which two had familial parkinsonism. All carriers shared an ancestral DNAJC13 p.Asn855Ser haplotype and claimed Dutch-German-Russian Mennonite heritage. DNAJC13 regulates the dynamics of clathrin coats on early endosomes. Cellular analysis shows that the mutation confers a toxic gain-of-function and impairs endosomal transport. DNAJC13 immunoreactivity was also noted within Lewy body inclusions. In late-onset disease which is most reminiscent of idiopathic PD subtle deficits in endosomal receptor-sorting/recycling are highlighted by the discovery of pathogenic mutations VPS35, LRRK2 and now DNAJC13. With this latest discovery, and from a neuronal perspective, a temporal and functional ecology is emerging that connects synaptic exo- and endocytosis, vesicular trafficking, endosomal recycling and the endo-lysosomal degradative pathway. Molecular deficits in these processes are genetically linked to the phenotypic spectrum of parkinsonism associated with Lewy body pathology.
Asunto(s)
Cuerpos de Lewy/genética , Chaperonas Moleculares/genética , Mutación/genética , Enfermedad de Parkinson/genética , Adulto , Edad de Inicio , Anciano , Secuencia de Bases , Estudios de Casos y Controles , Células Cultivadas , Endocitosis/genética , Endosomas/genética , Familia , Femenino , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Enfermedad por Cuerpos de Lewy/genética , Masculino , Persona de Mediana Edad , Chaperonas Moleculares/inmunología , Linaje , Proteínas Serina-Treonina Quinasas/genética , Alineación de Secuencia , Análisis de Secuencia de ADN , Proteínas de Transporte Vesicular/genéticaRESUMEN
OBJECTIVE: Amyotrophic lateral sclerosis/parkinsonism-dementia complex has been described in Guam, Western Papua, and the Kii Peninsula of Japan. The etiology and pathogenesis of this complex neurodegenerative disease remains enigmatic. METHODS: In this study, we have used targeted genomic sequencing to evaluate the contribution of genetic variability in the pathogenesis of amyotrophic lateral sclerosis, parkinsonism, and dementia in Guamanian Chamorros. RESULTS: Genes previously linked to or associated with amyotrophic lateral sclerosis, parkinsonism, dementia, and related neurodegenerative syndromes were sequenced in Chamorro subjects living in the Mariana Islands. Homozygous PINK1 p.L347P, heterozygous DCTN1 p.T54I, FUS p.P431L, and HTT (42 CAG repeats) were identified as pathogenic mutations. INTERPRETATION: The findings explain the clinical, pathologic, and genetic heterogeneity observed in some multi-incident families and contribute to the excess incidence of neurodegeneration previously reported on Guam.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Demencia/genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas del Tejido Nervioso/genética , Enfermedad de Parkinson/genética , Proteínas Quinasas/genética , Proteína FUS de Unión a ARN/genética , Adulto , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/epidemiología , Demencia/epidemiología , Complejo Dinactina , Guam/epidemiología , Humanos , Proteína Huntingtina , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/epidemiología , Linaje , SíndromeRESUMEN
Parkinson's disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The LRRK2 p.G2019S mutation causes PD in 42.5-68% of carriers by the age of 80 years. We hypothesise similarly intermediately penetrant mutations may present in multi-incident families with a generally strong family history of disease. We have analysed six multiplex families for missense variants using whole exome sequencing to find 32 rare heterozygous mutations shared amongst affected members. Included in these mutations was the KCNJ15 p.R28C variant, identified in five affected members of the same family, two elderly unaffected members of the same family, and two unrelated PD cases. Additionally, the SIPA1L1 p.R236Q variant was identified in three related affected members and an unrelated familial case. While the evidence presented here is not sufficient to assign causality to these rare variants, it does provide novel candidates for hypothesis testing in other modestly sized families with a strong family history. Future analysis will include characterisation of functional consequences and assessment of carriers in other familial cases.