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. Epub 2015 Feb 26.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apraxias / congenital
  • Child
  • Child, Preschool
  • Cogan Syndrome / genetics*
  • DNA Damage
  • DNA Repair
  • DNA Repair Enzymes / genetics*
  • DNA Repair Enzymes / metabolism
  • Female
  • Heterozygote
  • Homozygote
  • Humans
  • Infant
  • Male
  • Microcephaly / genetics
  • Mutation
  • Pedigree
  • Phenotype
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Spinocerebellar Ataxias / congenital
  • Spinocerebellar Degenerations / genetics*

Substances

  • PNKP protein, human
  • Phosphotransferases (Alcohol Group Acceptor)
  • DNA Repair Enzymes

Supplementary concepts

  • Apraxia, oculomotor, Cogan type
  • Spinocerebellar ataxia, autosomal recessive 1