Heterozygous PNPT1 Variants Cause Spinocerebellar Ataxia Type 25

Abstract

Objective: Dominant spinocerebellar ataxias (SCA) are characterized by genetic heterogeneity. Some mapped and named loci remain without a causal gene identified. Here we applied next generation sequencing (NGS) to uncover the genetic etiology of the SCA25 locus. Methods: Whole-exome and whole-genome sequencing were performed in families linked to SCA25, including the French family in which the SCA25 locus was originally mapped. Whole exome sequence data were interrogated in a cohort of 796 ataxia patients of unknown etiology. Results: The SCA25 phenotype spans a slowly evolving sensory and cerebellar ataxia, in most cases attributed to ganglionopathy. A pathogenic variant causing exon skipping was identified in the gene encoding Polyribonucleotide Nucleotidyltransferase PNPase 1 (PNPT1) located in the SCA25 linkage interval. A second splice variant in PNPT1 was detected in a large Australian family with a dominant ataxia also mapping to SCA25. An additional nonsense variant was detected in an unrelated individual with ataxia. Both nonsense and splice heterozygous variants result in premature stop codons, all located in the S1-domain of PNPase. In addition, an elevated type I interferon response was observed in blood from all affected heterozygous carriers tested. PNPase notably prevents the abnormal accumulation of

A Novel Pathogenic Variant in the SCA25-Related Gene Expanding the Etiology of Early-Onset and Progressive Cerebellar Ataxia in Childhood

“…Additional findings can include deafness (one patient), psychomotor delay as seen in our proband and scoliosis (three children). In time, patients often lose motor abilities: 2 cases, although still ambulant, were unable run, two required a wheelchair (one since adolescence, one at an unknown age), two a K-walker in childhood [2,3]. Our study confirms that SCA25 can indeed manifest in early childhood (occurring within the first three years of life) and contributes to the understanding of the natural history in pediatric patients.…”

“…Similar proportions of patients had childhood and adult onset; however, onset in early childhood (birth to 3 years) was observed in only one case. In the present report we describe a second patient who carried a novel PNPT1 variant and had onset of SCA25 already during toddler age [2]…”

“…Childhood onset can be a feature of this disease: to date, including the case presented here, 9 out of 18 SCA25 patients for whom information on the age at onset was available had childhood onset. Their phenotype is very variable (Table 1): age at onset ranges from 17 months to 10 years, with ataxic symptoms varying from mild to severe [2,3].…”

“…Among these there is SCA25, a SCA subtype which has only recently been better characterized. Indeed, Barbier et al identified the causal gene for this disease to be PNPT1, the mitochondrial olyribonucleotide nucleotidyltransferase 1, and described the associated clinical phenotype in a cohort of patients [2,3]. PNPT1 encodes for an exoribonuclease (PNPase) located in both the mitochondrial intermembrane space and matrix, involved in RNA import and in prevention of the accumulation of double stranded mtRNA in mitochondria [2].…”

“…Indeed, Barbier et al identified the causal gene for this disease to be PNPT1, the mitochondrial olyribonucleotide nucleotidyltransferase 1, and described the associated clinical phenotype in a cohort of patients [2,3]. PNPT1 encodes for an exoribonuclease (PNPase) located in both the mitochondrial intermembrane space and matrix, involved in RNA import and in prevention of the accumulation of double stranded mtRNA in mitochondria [2]. Interestingly, bi-allelic pathogenic variants in PNPT1 have been previously associated with different phenotypes, ranging from non-syndromic hearing loss to multisystem Leigh disease [4,5], with a recessive model of inheritance.…”