title: A mutation in the serine protease TMPRSS4 in a novel pediatric neurodegenerative disorder.
abstract: BACKGROUND
  To elucidate the genetic basis of a novel neurodegenerative disorder in an Old Order Amish pedigree by combining homozygosity mapping with exome sequencing.
  
  
  RESULTS
  We identified four individuals with an autosomal recessive condition affecting the central nervous system (CNS). Neuroimaging studies identified progressive global CNS tissue loss presenting early in life, associated with microcephaly, seizures, and psychomotor retardation; based on this, we named the condition Autosomal Recessive Cerebral Atrophy (ARCA). Using two unbiased genetic approaches, homozygosity mapping and exome sequencing, we narrowed the candidate region to chromosome 11q and identified the c.995C > T (p.Thr332Met) mutation in the TMPRSS4 gene. Sanger sequencing of additional relatives confirmed that the c.995C > T genotype segregates with the ARCA phenotype. Residue Thr332 is conserved across species and among various ethnic groups. The mutation is predicted to be deleterious, most likely due to a protein structure alteration as demonstrated with protein modelling.
  
  
  CONCLUSIONS
  This novel disease is the first to demonstrate a neurological role for a transmembrane serine proteases family member. This study demonstrates a proof-of-concept whereby combining exome sequencing with homozygosity mapping can find the genetic cause of a rare disease and acquire better understanding of a poorly described protein in human development.
authors: Robarts Research Institute, London, ON, Canada. hegele@robarts.ca.
authors: Piya
authors: P
authors: Lahiry
authors: Lemuel
authors: L
authors: Racacho
authors: Jian
authors: J
authors: Wang
authors: John F
authors: JF
authors: Robinson
authors: Gregory B
authors: GB
authors: Gloor
authors: C Anthony
authors: CA
authors: Rupar
authors: Victoria M
authors: VM
authors: Siu
authors: Dennis E
authors: DE
authors: Bulman
authors: Robert A
authors: RA
authors: Hegele
mesh_terms: D006801:Humans; D008279:Magnetic Resonance Imaging; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D012697:Serine Endopeptidases; C528837:TMPRSS4 protein, human
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