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Neurogenetics
Original article
Mitochondrial PITRM1 peptidase loss-of-function in childhood cerebellar atrophy
  1. Yeshaya Langer1,
  2. Adi Aran2,
  3. Suleyman Gulsuner3,
  4. Bassam Abu Libdeh4,
  5. Paul Renbaum5,
  6. Dario Brunetti6,7,
  7. Pedro-Filipe Teixeira8,
  8. Tom Walsh3,
  9. Sharon Zeligson5,
  10. Roberta Ruotolo9,
  11. Rachel Beeri5,
  12. Imad Dweikat4,
  13. Maher Shahrour4,
  14. Ariella Weinberg-Shukron5,
  15. Fouad Zahdeh5,
  16. Enrico Baruffini9,
  17. Elzbieta Glaser8,
  18. Mary-Claire King3,
  19. Ephrat Levy-Lahad10,
  20. Massimo Zeviani6,
  21. Reeval Segel11
  1. 1Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel
  2. 2Department of Pediatrics, Neuropediatrics Unit, Shaare Zedek Medical Center and Hebrew University-Hadassah School of Medicine, Jerusalem, Israel
  3. 3Departments of Medicine and Genome Sciences, University of Washington, Seattle, Washington, USA
  4. 4Departments of Pediatrics and Genetics, Makassed Hospital, Al-Quds University, Jerusalem, Israel
  5. 5Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel
  6. 6MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
  7. 7Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
  8. 8Department of Biochemistry and Biophysics, Arrhenius Laboratories for Natural Sciences, Stockholm University, Stockholm, Sweden
  9. 9Department of Chemistry, Life Sciences, and Environmental Sustainability, University of Parma, Parma, Italy
  10. 10Medical Genetics Institute, Shaare Zedek Medical Center, Hebrew University-Hadassah School of Medicine, Jerusalem, Israel
  11. 11Department of Pediatrics, Medical Genetics Institute, Shaare Zedek Medical Center, Hebrew University-Hadassah School of Medicine, Jerusalem, Israel
  1. Correspondence to Dr Reeval Segel, Department of Pediatrics, Medical Genetics Institute, Shaare Zedek Medical Center, Hebrew University-Hadassah School of Medicine, Jerusalem 91031, Israel; reevals{at}szmc.org.il

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.

  • cerebellar atrophy
  • whole exome sequencing
  • PITML
  • mitochondria
  • next generation sequencing

https://doi.org/10.1136/jmedgenet-2018-105330

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    Footnotes

    • YL and AA contributed equally.

    • Contributors YL participated in conceptualising the study, examined the participants, collected DNA samples and clinical data; performed genetic testing and analysis, wrote the first draft and approved final manuscript version. AA participated in conceptualising the study, identified and recruited patients and family members examined the participants, collected DNA samples and clinical data; wrote the first draft with YL and approved final manuscript version. SG performed genetic analysis and interpretations and wrote sections of the manuscript. BAL identified and recruited patients and family members examined the participants, collected DNA samples and clinical data and wrote sections of the manuscript. PR participated in conceptualising the study, provided insights about the hypothesis and directed genetic testing and analysis. DB performed genetic analysis and interpretations and wrote sections of the manuscript. P-FT performed peptide assays and wrote sections of the manuscript. TW performed genetic analysis and interpretations. SZ performed genetic analysis and interpretations. RR designed and constructed the plasmid bearing the mitochomdrial-targeted A42 peptide coding sequence. RB performed genetic analysis and interpretations and wrote sections of the manuscript. ID recruited patients and family members, examined the participants, collected DNA samples and clinical data. MS recruited patients and family members examined the participants, collected DNA samples and clinical data. AW-S performed genetic analysis and interpretations. FZ performed genetic analysis and interpretations. EB designed and performed the experiments in yeast and wrote sections of the manuscript. EG directed peptide assays and wrote sections of the manuscript. M-CK participated in conceptualising the study; directed genomic analysis, interpreted results, obtained funding and critically revised the manuscript. EL-L participated in conceptualising the study; directed genetic testing, analysis and interpretation of the results; obtained funding and critically revised the manuscript. ZM directed genetic analysis and interpretations and wrote sections of the manuscript. RS participated in conceptualising the study, identified and recruited patients and family members, examined the participants, collected DNA samples and clinical data, directed genetic testing, analysis and interpretation of the results, wrote the first draft and approved final manuscript version.

    • Funding This study was supported by grants TA-MOU-10-M30-021 from the US Agency for International Development programme for Middle East Regional Cooperation to EL-L; R01MH083989 from the National Institutes of Health to SG and M-CK; DN2015-04833 from the Swedish Research Council and the Alzheimer Foundation to EG; FP7-322424 from the European Research Council, Mito-ND-RG89471 from the Centre of Excellence for Neurodegeneration, NRJ-Institut de France Grant and MRC core grant to MZ and by a gift from the Hassenfeld family to Shaare Zedek Medical Center.

    • Competing interests None declared.

    • Patient consent Not required.

    • Ethics approval The study was approved by the Internal Review Board of Shaare Zedek Medical Center, by the University of Washington Human Subjects Division and by the Israel National Ethics Committee for Genetic Studies (protocol 20/10).

    • Provenance and peer review Not commissioned; externally peer reviewed.