RT Journal Article SR Electronic T1 Mitochondrial PITRM1 peptidase loss-of-function in childhood cerebellar atrophy JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 599 OP 606 DO 10.1136/jmedgenet-2018-105330 VO 55 IS 9 A1 Langer, Yeshaya A1 Aran, Adi A1 Gulsuner, Suleyman A1 Abu Libdeh, Bassam A1 Renbaum, Paul A1 Brunetti, Dario A1 Teixeira, Pedro-Filipe A1 Walsh, Tom A1 Zeligson, Sharon A1 Ruotolo, Roberta A1 Beeri, Rachel A1 Dweikat, Imad A1 Shahrour, Maher A1 Weinberg-Shukron, Ariella A1 Zahdeh, Fouad A1 Baruffini, Enrico A1 Glaser, Elzbieta A1 King, Mary-Claire A1 Levy-Lahad, Ephrat A1 Zeviani, Massimo A1 Segel, Reeval YR 2018 UL http://jmg.bmj.com/content/55/9/599.abstract AB Objective To identify the genetic basis of a childhood-onset syndrome of variable severity characterised by progressive spinocerebellar ataxia, mental retardation, psychotic episodes and cerebellar atrophy.Methods Identification of the underlying mutations by whole exome and whole genome sequencing. Consequences were examined in patients’ cells and in yeast.Results Two brothers from a consanguineous Palestinian family presented with progressive spinocerebellar ataxia, mental retardation and psychotic episodes. Serial brain imaging showed severe progressive cerebellar atrophy. Whole exome sequencing revealed a novel mutation: pitrilysin metallopeptidase 1 (PITRM1) c.2795C>T, p.T931M, homozygous in the affected children and resulting in 95% reduction in PITRM1 protein. Whole genome sequencing revealed a chromosome X structural rearrangement that also segregated with the disease. Independently, two siblings from a second Palestinian family presented with similar, somewhat milder symptoms and the same PITRM1 mutation on a shared haplotype. PITRM1T931M carrier frequency was 0.027 (3/110) in the village of the first family evaluated, and 0/300 among Palestinians from other locales. PITRM1 is a mitochondrial matrix enzyme that degrades 10–65 amino acid oligopeptides, including the mitochondrial fraction of amyloid-beta peptide. Analysis of peptide cleavage activity by the PITRM1T931M protein revealed a significant decrease in the degradation capacity specifically of peptides ≥40 amino acids.Conclusion PITRM1T931M results in childhood-onset recessive cerebellar pathology. Severity of PITRM1-related disease may be affected by the degree of impairment in cleavage of mitochondrial long peptides. Disruption and deletion of X linked regulatory segments may also contribute to severity.