title: Identification of a novel homozygous mutation Arg459Pro in SYNJ1 gene of an Indian family with autosomal recessive juvenile Parkinsonism.
abstract: A novel homozygous missense mutation (c.773G > A, p.Arg258Gln) in Synaptojanin 1 (SYNJ1, 21q22.2) has recently been reported in two Italian and one Iranian consanguineous families with autosomal recessive juvenile Parkinsonism (ARJP). Contribution of this synaptic gene related to Parkinsonism phenotypes in other populations still remains unidentified.
  
  
  
  An ARJP family with two affected siblings characterized by frequent tremor with bradykinesia and rigidity was recruited in this study. Both siblings showed intense dyskinesia and dystonia on administration of Syndopa. The family was analyzed for both mutations and exon dosage variations in PARKIN, PINK1 and DJ1. Further, whole exome sequencing was performed in two affected and one unaffected sibling in the family.
  
  
  
  We identified a novel homozygous mutation (c.1376C > G, p.Arg459Pro) in SYNJ1 segregating in this family. This p.Arg459Pro mutation was not observed in 285 additional Parkinson disease (PD) samples (32 familial, 81 early onset and 172 late onset) screened by PCR-Sanger-sequencing. It was also absent in dbSNP, 1000 Genomes, ExAC, NHLBI-ESP database and in >250 ethnically matched exomes available in our laboratory. The arginine residue is highly conserved across species and predicted to be damaging by several in silico tools. As with the previous mutation p.Arg258Gln, p.Arg459Pro is also present in Sac 1 domain of SYNJ1 wherein p.Arg258Gln mutation has already been described to impair the phosphatase activity.
  
  
  
  We report another novel mutation in SYNJ1 of an Indian consanguineous ARJP family. Finding an additional mutation in this gene further supports the involvement of SYNJ1 in PD pathogenesis across different ethnicities.
authors: Department of Genetics, University of Delhi South Campus, New Delhi 110021, India.
authors: Laxmi
authors: L
authors: Kirola
authors: Department of Neurology, All India Institute of Medical Sciences, New Delhi 110029, India.
authors: Madhuri
authors: M
authors: Behari
authors: Department of Neurology, All India Institute of Medical Sciences, New Delhi 110029, India.
authors: Chandan
authors: C
authors: Shishir
authors: Department of Genetics, University of Delhi South Campus, New Delhi 110021, India. Electronic address: thelmabk@gmail.com.
authors: B K
authors: BK
authors: Thelma
mesh_terms: D000328:Adult; D001120:Arginine / Q000235:genetics*; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D007194:India; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000000981:diagnostic imaging / Q000235:genetics*; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D011392:Proline / Q000235:genetics*; D055815:Young Adult; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D001120:Arginine; D010744:Phosphoric Monoester Hydrolases; D011392:Proline; D000099182:Phosphoinositide 5-Phosphatases
keywords: Autosomal recessive juvenile Parkinsonism; Mutation screening; Synaptojanin 1; Whole exome sequencing