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 display...

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Bibliographic Details
Published in:American journal of human genetics 2015-03, Vol.96 (3), p.474-479
Main Authors: Bras, Jose, Alonso, Isabel, Barbot, Clara, Costa, Maria Manuela, Darwent, Lee, Orme, Tatiana, Sequeiros, Jorge, Hardy, John, Coutinho, Paula, Guerreiro, Rita
Format: Article
Language:English
Subjects:
Apraxias - congenital
Ataxia
Child
Child, Preschool
Cogan Syndrome - genetics
DNA Damage
DNA Repair
DNA Repair Enzymes - genetics
DNA Repair Enzymes - metabolism
Families & family life
Female
Genetic disorders
Genotype & phenotype
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
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Summary: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.
ISSN:0002-9297
1537-6605
DOI:10.1016/j.ajhg.2015.01.005