title: Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination.
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.
authors: 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.
authors: Tojo
authors: T
authors: Nakayama
authors: 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.
authors: Almundher
authors: A
authors: Al-Maawali
authors: 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.
authors: Malak
authors: M
authors: El-Quessny
authors: National Genetics Center, Directorate General of Health Affairs, Ministry of Health, Muscat 113, Oman.
authors: Anna
authors: A
authors: Rajab
authors: Department of Pediatrics, Al-Makassed Islamic Charitable Society Hospital, Jerusalem 91220; Faculty of Medicine, Al-Quds University, Jerusalem 90612.
authors: Samir
authors: S
authors: Khalil
authors: 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.
authors: Joan M
authors: JM
authors: Stoler
authors: 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.
authors: Wen-Hann
authors: WH
authors: Tan
authors: 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.
authors: Ramzi
authors: R
authors: Nasir
authors: 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.
authors: Klaus
authors: K
authors: Schmitz-Abe
authors: 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.
authors: R Sean
authors: RS
authors: Hill
authors: 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.
authors: Jennifer N
authors: JN
authors: Partlow
authors: 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.
authors: Muna
authors: M
authors: Al-Saffar
authors: 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.
authors: Sarah
authors: S
authors: Servattalab
authors: Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
authors: Christopher M
authors: CM
authors: LaCoursiere
authors: Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
authors: Dimira E
authors: DE
authors: Tambunan
authors: 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.
authors: Michael E
authors: ME
authors: Coulter
authors: 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.
authors: Princess C
authors: PC
authors: Elhosary
authors: Cellular Neuroscience Core, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA.
authors: Grzegorz
authors: G
authors: Gorski
authors: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: A James
authors: AJ
authors: Barkovich
authors: 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.
authors: Kyriacos
authors: K
authors: Markianos
authors: 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.
authors: Annapurna
authors: A
authors: Poduri
authors: 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.
authors: Ganeshwaran H
authors: GH
authors: Mochida
mesh_terms: D026922:Amino Acid Transport Systems, Acidic / Q000172:deficiency* / Q000235:genetics; D017920:Antiporters / Q000172:deficiency* / Q000235:genetics; D005260:Female; D005838:Genotype; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics* / Q000473:pathology; D006720:Homozygote; D006801:Humans; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D011596:Psychomotor Disorders / Q000235:genetics* / Q000473:pathology; D011762:Pyrroline Carboxylate Reductases / Q000235:genetics*; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D017920:Antiporters; D011762:Pyrroline Carboxylate Reductases; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase; C000620304:PYCR2 protein, human