Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis

Abstract

Neuronal ceroid lipofuscinoses (NCLs) comprise a heterogeneous group of metabolic storage diseases that present with the accumulation of autofluorescent lipopigment, neurodegeneration and premature death. Nine genes have been thus far identified as the cause of different types of NCL, with ages at onset ranging from around birth to adult, although the underlying etiology of the disease still remains elusive. We present a family with typical NCL pathology in which we performed exome sequencing and identified a single homozygous mutation in ATP13A2 that fully segregates with disease within the family. Mutations in ATP13A2 are a known cause of Kufor-Rakeb syndrome (KRS), a rare parkinsonian phenotype with juvenile onset. These data show that NCL and KRS may share etiological features and implicate the lysosomal pathway in Parkinson's disease.

Figure 1.

Pedigree of the family studied. Pedigree showing complete segregation of p.M810R mutation in ATP13A2 in the available family members. T is the reference allele, while G represents the mutation.

Figure 2.

Identification of a homozygous mutation in ATP13A2. Figure showing the region on chromosome 1 where ATP13A2 is located, with the coverage and variant calling obtained from exome sequencing at the p.M810R locus for one affected sibling. Also shown are Sanger sequencing traces for one affected and two unaffected samples from the family and the protein sequence comparison displaying high conservation between species. The top panel on the chromatogram shows the affected individual (homozygous G at the position), while the two bottom panels show unaffected individuals (one homozygous wild-type and one heterozygous).