Genetic study of a Chinese pedigree with early onset Parkinson’s disease caused by novel compound heterozygous mutations in PARKIN gene

Abstract

Objective: To explore the genetic basis for a Chinese pedigree where two siblings were afected with early-onset Parkinson's disease (EOPD). Methods: Clinical examinations and genomic analyses were performed on ive subjects belonging to two generations of a Han Chinese family. Target regions capture and high throughput sequencing were used to screen these genes associated with Parkinson's disease (PD), tremor, spinocerebellar ataxia, and dystonia. The multiplex ligation dependent probe ampliication (MLPA) method was applied to detect rearrangements and large deletion in PARKIN exons. Results: Two family members were diagnosed with PD by clinical manifestations. Compound heterozygous mutations, consisting of a fragment deletion in exon 2 and 3 of the PARKIN gene, identiied by MLPA in II-3, II-5. Individual exon2 deletion mutations were detected in II-1 while individual exon3 deletion mutations were detected in two thirds generations (III-5, III-6). The compound heterozygous mutations have co-segregated with the disease in the pedigree. Other mutations in some genes associated with PD, tremor, dystonia and other movement disorders were not detected. Conclusion:A novel compound heterozygous deletion mutations of the PARKIN gene were identiied in a Chinese pedigree and might represent a cause of familial EOPD with autosomal dominant inheritance.Early-onset Parkinson's disease (PD) with PARKIN gene mutation has genetic and clinical heterogeneity.

A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1

“…Since then, intensive research efforts have been made to understand Parkin function and structure. With an increasing number of identified PD patient mutations throughout the PRKN sequence ( Zhang et al, 2021 ; Li et al, 2021 ; Jiang et al, 2020 ; Kasten et al, 2018 ; Taghavi et al, 2018 ; Tan et al, 2019 ), it became clear that all domains, and even supposedly disordered regions of Parkin are important for its function. Parkin is a RING-BetweenRING-RING (RBR) E3 ubiquitin ligase ( Wenzel et al, 2011 ), composed of five domains ( Riley et al, 2013 ): an N-terminal ubiquitin-like domain (Ubl), connected by a 65-residue flexible region (linker) to a unique to Parkin RING0 domain, which, together with RING1 and BRcat (IBR) constitute a more rigid ‘core’ of Parkin ( Fig.…”