Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4.
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.
Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
Jose
J
Bras
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.
Isabel
I
Alonso
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.
Clara
C
Barbot
Hospital Pedro Hispano, Unidade Local de Saúde de Matosinhos, Matosinhos 4454-509, Portugal.
Maria Manuela
MM
Costa
Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
Lee
L
Darwent
Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
Tatiana
T
Orme
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.
Jorge
J
Sequeiros
Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
John
J
Hardy
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.
Paula
P
Coutinho
Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK. Electronic address: r.guerreiro@ucl.ac.uk.
Rita
R
Guerreiro
D001072:Apraxias / Q000151:congenital; D002648:Child; D002675:Child, Preschool; D055952:Cogan Syndrome / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008831:Microcephaly / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000151:congenital; D013132:Spinocerebellar Degenerations / Q000235:genetics*
C530380:PNKP protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); D045643:DNA Repair Enzymes