title: Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis.
abstract: Polymicrogyria (PMG) is a structural brain abnormality involving the cerebral cortex that results from impaired neuronal migration and although several genes have been implicated, many cases remain unsolved. In this study, exome sequencing in a family where three fetuses had all been diagnosed with PMG and cerebellar hypoplasia allowed us to identify regions of the genome for which both chromosomes were shared identical-by-descent, reducing the search space for causative variants to 8.6% of the genome. In these regions, the only plausibly pathogenic mutations were compound heterozygous variants in PI4KA, which Sanger sequencing confirmed segregated consistent with autosomal recessive inheritance. The paternally transmitted variant predicted a premature stop mutation (c.2386C>T; p.R796X), whereas the maternally transmitted variant predicted a missense substitution (c.5560G>A; p.D1854N) at a conserved residue within the catalytic domain. Functional studies using expressed wild-type or mutant PI4KA enzyme confirmed the importance of p.D1854 for kinase activity. Our results emphasize the importance of phosphoinositide signalling in early brain development.
authors: National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors: Alistair T
authors: AT
authors: Pagnamenta
authors: National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors: Malcolm F
authors: MF
authors: Howard
authors: Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Eva
authors: E
authors: Wisniewski
authors: National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors: Niko
authors: N
authors: Popitsch
authors: National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors: Samantha J L
authors: SJ
authors: Knight
authors: Institute of Molecular Pathology, Vienna 1030, Austria.
authors: David A
authors: DA
authors: Keays
authors: Department of Neuroradiology.
authors: Gerardine
authors: G
authors: Quaghebeur
authors: West Midlands Regional Clinical Genetics Service, Clinical Genetics Unit and.
authors: Helen
authors: H
authors: Cox
authors: Department of Histopathology, Birmingham Women's Hospital NHS Foundation Trust, Birmingham B15 2TG, UK.
authors: Phillip
authors: P
authors: Cox
authors: Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Tamas
authors: T
authors: Balla
authors: National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors: Jenny C
authors: JC
authors: Taylor
authors: Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford OX3 9DU, UK, usha.kini@ouh.nhs.uk.
authors: Usha
authors: U
authors: Kini
mesh_terms: D000595:Amino Acid Sequence; D001176:Arthrogryposis / Q000196:embryology / Q000201:enzymology* / Q000235:genetics; D001483:Base Sequence; D001921:Brain / Q000196:embryology / Q000201:enzymology; D002531:Cerebellum / Q000002:abnormalities* / Q000196:embryology / Q000201:enzymology; D002658:Developmental Disabilities / Q000201:enzymology / Q000235:genetics; D059472:Exome; D005260:Female; D005315:Fetal Diseases / Q000201:enzymology* / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D008297:Male; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009421:Nervous System Malformations / Q000196:embryology / Q000201:enzymology* / Q000235:genetics; D010375:Pedigree; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000235:genetics*; D065706:Polymicrogyria / Q000196:embryology / Q000201:enzymology* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D016415:Sequence Alignment
chemical_list: D015778:Minor Histocompatibility Antigens; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase