Mitochondrial PITRM1 peptidase loss-of-function in childhood cerebellar atrophy

Journal of Medical Genetics
Yeshaya LangerReeval Segel

Abstract

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. Identification of the underlying mutations by whole exome and whole genome sequencing. Consequences were examined in patients' cells and in yeast. 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 oligo...Continue Reading

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Citations

Jul 13, 2018·CNS Neuroscience & Therapeutics·Josef Finsterer, Sinda Zarrouk-Mahjoub
Jun 4, 2020·The FEBS Journal·Cansu KücükköseFriederike-Nora Vögtle
Feb 23, 2020·Annual Review of Biochemistry·Soni DeshwalThomas Langer
Jan 17, 2021·FEBS Letters·Maria Gomez-Fabra Gala, Friederike-Nora Vögtle
Jan 16, 2021·International Journal of Molecular Sciences·Margarita A SazonovaIgor A Sobenin
Jun 18, 2021·Journal of Medical Genetics·Deborah TolomeoFilippo M M Santorelli
Aug 7, 2021·Biomedicines·Dario BrunettiMassimo Zeviani
Aug 8, 2021·International Journal of Molecular Sciences·Joseph E FriedlanderHui Feng

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