Repository logo
 

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

Accepted version
Peer-reviewed

No Thumbnail Available

Type

Article

Change log

Authors

Langer, Yeshaya 
Aran, Adi 
Gulsuner, Suleyman 
Abu Libdeh, Bassam 
Renbaum, Paul 

Abstract

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.

Description

Keywords

PITML, cerebellar atrophy, mitochondria, next generation sequencing, whole exome sequencing, Adolescent, Age of Onset, Arabs, Atrophy, Cerebellar Diseases, Cerebellum, Child, Humans, Loss of Function Mutation, Male, Metalloendopeptidases, Mitochondria, Mitochondrial Proteins, Pedigree, Exome Sequencing, Whole Genome Sequencing, Young Adult

Journal Title

J Med Genet

Conference Name

Journal ISSN

0022-2593
1468-6244

Volume Title

55

Publisher

BMJ
Sponsorship
Medical Research Council (MC_EX_MR/P007031/1)
European Research Council (322424)