PT - JOURNAL ARTICLE AU - Langer, Yeshaya AU - Aran, Adi AU - Gulsuner, Suleyman AU - Abu Libdeh, Bassam AU - Renbaum, Paul AU - Brunetti, Dario AU - Teixeira, Pedro-Filipe AU - Walsh, Tom AU - Zeligson, Sharon AU - Ruotolo, Roberta AU - Beeri, Rachel AU - Dweikat, Imad AU - Shahrour, Maher AU - Weinberg-Shukron, Ariella AU - Zahdeh, Fouad AU - Baruffini, Enrico AU - Glaser, Elzbieta AU - King, Mary-Claire AU - Levy-Lahad, Ephrat AU - Zeviani, Massimo AU - Segel, Reeval TI - Mitochondrial <em>PITRM1</em> peptidase loss-of-function in childhood cerebellar atrophy AID - 10.1136/jmedgenet-2018-105330 DP - 2018 Sep 01 TA - Journal of Medical Genetics PG - 599--606 VI - 55 IP - 9 4099 - http://jmg.bmj.com/content/55/9/599.short 4100 - http://jmg.bmj.com/content/55/9/599.full SO - J Med Genet2018 Sep 01; 55 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&gt;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.