2. Academic Validation
  3. Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination

Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination

  • Am J Hum Genet. 2015 May 7;96(5):709-19. doi: 10.1016/j.ajhg.2015.03.003.
Tojo Nakayama 1,  Almundher Al-Maawali 2,  Malak El-Quessny 3,  Anna Rajab 4,  Samir Khalil 5,  Joan M Stoler 6,  Wen-Hann Tan 6,  Ramzi Nasir 7,  Klaus Schmitz-Abe 8,  R Sean Hill 9,  Jennifer N Partlow 9,  Muna Al-Saffar 10,  Sarah Servattalab 9,  Christopher M LaCoursiere 11,  Dimira E Tambunan 11,  Michael E Coulter 12,  Princess C Elhosary 13,  Grzegorz Gorski 14,  A James Barkovich 15,  Kyriacos Markianos 8,  Annapurna Poduri 16,  Ganeshwaran H Mochida 17
Affiliations

Affiliations

  • 1 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Genetics, College of Medicine and Health Science, Sultan Qaboos University, Muscat 123, Oman.
  • 3 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA.
  • 4 National Genetics Center, Directorate General of Health Affairs, Ministry of Health, Muscat 113, Oman.
  • 5 Department of Pediatrics, Al-Makassed Islamic Charitable Society Hospital, Jerusalem 91220; Faculty of Medicine, Al-Quds University, Jerusalem 90612.
  • 6 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
  • 7 Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Division of Developmental Medicine, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • 8 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 9 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
  • 10 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al-Ain, United Arab Emirates.
  • 11 Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 12 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
  • 13 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 14 Cellular Neuroscience Core, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA.
  • 15 Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 16 Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; Epilepsy Genetics Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
  • 17 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: ganesh.mochida@childrens.harvard.edu.
PMID: 25865492 DOI: 10.1016/j.ajhg.2015.03.003
Abstract

Despite recent advances in understanding the genetic bases of microcephaly, a large number of cases of microcephaly remain unexplained, suggesting that many microcephaly syndromes and associated genes have yet to be identified. Here, we report mutations in PYCR2, which encodes an Enzyme in the proline biosynthesis pathway, as the cause of a unique syndrome characterized by postnatal microcephaly, hypomyelination, and reduced cerebral white-matter volume. Linkage mapping and whole-exome Sequencing identified homozygous mutations (c.355C>T [p.Arg119Cys] and c.751C>T [p.Arg251Cys]) in PYCR2 in the affected individuals of two consanguineous families. A lymphoblastoid cell line from one affected individual showed a strong reduction in the amount of PYCR2. When mutant cDNAs were transfected into HEK293FT cells, both variant proteins retained normal mitochondrial localization but had lower amounts than the wild-type protein, suggesting that the variant proteins were less stable. A PYCR2-deficient HEK293FT cell line generated by genome editing with the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system showed that PYCR2 loss of function led to decreased mitochondrial membrane potential and increased susceptibility to Apoptosis under oxidative stress. Morpholino-based knockdown of a zebrafish PYCR2 ortholog, pycr1b, recapitulated the human microcephaly phenotype, which was rescued by wild-type human PYCR2 mRNA, but not by mutant mRNAs, further supporting the pathogenicity of the identified variants. Hypomyelination and the absence of lax, wrinkly skin distinguishes this condition from that caused by previously reported mutations in the gene encoding PYCR2's isozyme, PYCR1, suggesting a unique and indispensable role for PYCR2 in the human CNS during development.

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