2. Academic Validation
  3. Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4

Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4

  • Am J Hum Genet. 2015 Mar 5;96(3):474-9. doi: 10.1016/j.ajhg.2015.01.005.
Jose Bras 1,  Isabel Alonso 2,  Clara Barbot 2,  Maria Manuela Costa 3,  Lee Darwent 1,  Tatiana Orme 1,  Jorge Sequeiros 2,  John Hardy 1,  Paula Coutinho 2,  Rita Guerreiro 4
Affiliations

Affiliations

  • 1 Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
  • 2 Center for Predictive and Preventive Genetics, Institute for Molecular and Cell Biology, University of Porto, Porto 4150-180, Portugal; Unidade de Investigação Genética e Epidemiológica em Doenças Neurológicas Research Group, Institute for Molecular and Cell Biology, University of Porto, Porto 4150-180, Portugal; Instituto de Investigação e Inovação em Saúde, University of Porto, Porto 4150-180, Portugal.
  • 3 Hospital Pedro Hispano, Unidade Local de Saúde de Matosinhos, Matosinhos 4454-509, Portugal.
  • 4 Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK. Electronic address: [email protected].
PMID: 25728773 DOI: 10.1016/j.ajhg.2015.01.005
Abstract

Hereditary autosomal-recessive cerebellar ataxias are a genetically and clinically heterogeneous group of disorders. We used homozygosity mapping and exome sequencing to study a cohort of nine Portuguese families who were identified during a nationwide, population-based, systematic survey as displaying a consistent phenotype of recessive ataxia with oculomotor apraxia (AOA). The integration of data from these analyses led to the identification of the same homozygous PNKP (polynucleotide kinase 3'-phosphatase) mutation, c.1123G>T (p.Gly375Trp), in three of the studied families. When analyzing this particular gene in the exome sequencing data from the remaining cohort, we identified homozygous or compound-heterozygous mutations in five other families. PNKP is a dual-function Enzyme with a key role in different pathways of DNA-damage repair. Mutations in this gene have previously been associated with an autosomal-recessive syndrome characterized by microcephaly; early-onset, intractable seizures; and developmental delay (MCSZ). The finding of PNKP mutations associated with recessive AOA extends the phenotype associated with this gene and identifies a fourth locus that causes AOA. These data confirm that MCSZ and some forms of ataxia share etiological features, most likely reflecting the role of PNKP in DNA-repair mechanisms.

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