title: Discovery of a frameshift mutation in podocalyxin-like (PODXL) gene, coding for a neural adhesion molecule, as causal for autosomal-recessive juvenile Parkinsonism.
abstract: Mutations in known genes for inherited forms of Parkinson's disease (PD) account for <30% of familial PD (FPD) implying that more causal gene(s) remain to be identified. We attempted to discover the putative causal variant in an Indian family with autosomal-recessive juvenile Parkinsonism (ARJP), tested negative for mutations in PARK2, PINK1 and DJ1.
  
  
  
  Whole exomes of two affected siblings were sequenced. Variants prioritised were screened for segregation with disease in the family by targeted sequencing. Gene thus identified was screened for index/additional exonic mutations, if any, in an independent PD cohort by PCR sequencing. Variants observed were functionally validated in differentiated PC12 cells.
  
  
  
  A novel homozygous frameshift mutation, c.89_90insGTCGCCCC in exon 1 of podocalyxin-like gene (PODXL, 7q32-33), resulting in loss of protein, segregated with disease in the family. Mutant allele was absent in 186 healthy controls screened by PCR sequencing and in control exomes available in the laboratory and public databases. Screening of additional 212 sporadic and 68 FPD cases identified three novel heterozygous missense variants namely c.1285C>A, c.1118G>A and c.881G>A in three unrelated cases. Significant differences in neurite branching and length (p<0.0001) were observed in PC12 cells with wild-type and mutant constructs.
  
  
  
  Based on the genetic and functional evidence in this study and literature support on the role of PODXL in neural development, a novel frameshift mutation in PODXL seems to be the likely cause of ARJP in this family. This is the first report suggesting the possible role of a neurodevelopmental pathway in PD aetiology.
authors: Department of Genetics, University of Delhi South Campus, New Delhi, India.
authors: Sumedha
authors: S
authors: Sudhaman
authors: Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.
authors: Kameshwar
authors: K
authors: Prasad
authors: Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.
authors: Madhuri
authors: M
authors: Behari
authors: Parkinson's and Ageing Research Foundation, Bengaluru, Karnataka, India.
authors: Uday B
authors: UB
authors: Muthane
authors: Regional Center for Biotechnology, Faridabad, Haryana, India.
authors: Ramesh C
authors: RC
authors: Juyal
authors: Department of Genetics, University of Delhi South Campus, New Delhi, India.
authors: B K
authors: BK
authors: Thelma
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D045744:Cell Line, Tumor; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D016716:PC12 Cells; D010300:Parkinson Disease / Q000235:genetics*; D051381:Rats; D012795:Sialoglycoproteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D012795:Sialoglycoproteins; C001643:podocalyxin
keywords: Clinical genetics; Genetics; Genome-wide; Neurosciences; Parkinson-s disease