Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4

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.

Figure 1

Pedigrees of the Portuguese Families In which AOA-Affected Members Had PNKP Mutations and Protein Representation with the Location of the Variants Found to Be Associated with Different Phenotypes Black symbols represent individuals affected by AOA. An arrow indicates the index individual in each family. Mutation segregation with disease is indicated underneath each symbol; all unaffected family members carry either a single variant (wt/mut) or no variants (wt/wt), and all affected individuals harbor mutations in homozygosity or compound heterozygosity. In the lower panel, PNKP (RefSeq NP_009185.2) is represented with the depicted regions as predicted by UniProtKB (Q96T60). Variants found in this study are represented in black and are all located in or adjacent to the kinase region of the protein. Variants previously identified in individuals with MCSZ are represented in gray. An additional 17-bp intron 15 deletion was reported in one family, which is not represented here. The variant p.Thr424Glyfs^∗49 (in orange) has been previously associated with MSCZ and with progressive cerebellar atrophy and polyneuropathy. The same change was identified in compound heterozygosity with p.Gly375Trp in family 1. Targeted resequencing has also identified the p.Pro20Ser (c.58G>A) variant in an individual with epileptic encephalopathy; this variant was considered to be pathogenic in the homozygous state but had previously been identified in the Exome Variant Server (overall MAF of 0.9%) and dbSNP databases and classified as benign in ClinVar.