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

J Med Genet. 2018 Sep;55(9):599-606. doi: 10.1136/jmedgenet-2018-105330.

Yeshaya Langer ^# ¹, Adi Aran ^# ², Suleyman Gulsuner ³, Bassam Abu Libdeh ⁴, Paul Renbaum ⁵, Dario Brunetti ⁶ ⁷, Pedro-Filipe Teixeira ⁸, Tom Walsh ³, Sharon Zeligson ⁵, Roberta Ruotolo ⁹, Rachel Beeri ⁵, Imad Dweikat ⁴, Maher Shahrour ⁴, Ariella Weinberg-Shukron ⁵, Fouad Zahdeh ⁵, Enrico Baruffini ⁹, Elzbieta Glaser ⁸, Mary-Claire King ³, Ephrat Levy-Lahad ¹⁰, Massimo Zeviani ⁶, Reeval Segel ¹¹

Affiliations

1 Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel.
2 Department of Pediatrics, Neuropediatrics Unit, Shaare Zedek Medical Center and Hebrew University-Hadassah School of Medicine, Jerusalem, Israel.
3 Departments of Medicine and Genome Sciences, University of Washington, Seattle, Washington, USA.
4 Departments of Pediatrics and Genetics, Makassed Hospital, Al-Quds University, Jerusalem, Israel.
5 Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
6 MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
7 Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
8 Department of Biochemistry and Biophysics, Arrhenius Laboratories for Natural Sciences, Stockholm University, Stockholm, Sweden.
9 Department of Chemistry, Life Sciences, and Environmental Sustainability, University of Parma, Parma, Italy.
10 Medical Genetics Institute, Shaare Zedek Medical Center, Hebrew University-Hadassah School of Medicine, Jerusalem, Israel.
11 Department of Pediatrics, Medical Genetics Institute, Shaare Zedek Medical Center, Hebrew University-Hadassah School of Medicine, Jerusalem, Israel.
# Contributed equally.

PMID: 29764912 DOI: 10.1136/jmedgenet-2018-105330

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.

Keywords

PITML; cerebellar atrophy; mitochondria; next generation sequencing; whole exome sequencing.

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