title: Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly.
abstract: Cobblestone lissencephaly (COB) is a severe brain malformation in which overmigration of neurons and glial cells into the arachnoid space results in the formation of cortical dysplasia. COB occurs in a wide range of genetic disorders known as dystroglycanopathies, which are congenital muscular dystrophies associated with brain and eye anomalies and range from Walker-Warburg syndrome to Fukuyama congenital muscular dystrophy. Each of these conditions has been associated with alpha-dystroglycan defects or with mutations in genes encoding basement membrane components, which are known to interact with alpha-dystroglycan. Our screening of a cohort of 25 families with recessive forms of COB identified six families affected by biallelic mutations in TMTC3 (encoding transmembrane and tetratricopeptide repeat containing 3), a gene without obvious functional connections to alpha-dystroglycan. Most affected individuals showed brainstem and cerebellum hypoplasia, as well as ventriculomegaly. However, the minority of the affected individuals had eye defects or elevated muscle creatine phosphokinase, separating the TMTC3 COB phenotype from typical congenital muscular dystrophies. Our data suggest that loss of TMTC3 causes COB with minimal eye or muscle involvement.
authors: Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA.
authors: Julie
authors: J
authors: Jerber
authors: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
authors: Maha S
authors: MS
authors: Zaki
authors: Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21453, Saudi Arabia; Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah 21453, Saudi Arabia.
authors: Jumana Y
authors: JY
authors: Al-Aama
authors: Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA.
authors: Rasim Ozgur
authors: RO
authors: Rosti
authors: Clinical and Metabolic Genetics Section, Department of Pediatrics, Hamad Medical Corporation, PO Box 3050, Doha, Qatar; Weill Cornell Medical College, Qatar, Education City, PO Box 24144, Doha, Qatar.
authors: Tawfeg
authors: T
authors: Ben-Omran
authors: Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA.
authors: Esra
authors: E
authors: Dikoglu
authors: Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA.
authors: Jennifer L
authors: JL
authors: Silhavy
authors: Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, NY 10065, USA.
authors: Caner
authors: C
authors: Caglar
authors: Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA.
authors: Damir
authors: D
authors: Musaev
authors: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany.
authors: Beate
authors: B
authors: Albrecht
authors: Howard Hughes Medical Institute, Departments of Neurology, Internal Medicine, and Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242-1101, USA.
authors: Kevin P
authors: KP
authors: Campbell
authors: Howard Hughes Medical Institute, Departments of Neurology, Internal Medicine, and Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242-1101, USA.
authors: Tobias
authors: T
authors: Willer
authors: Clinical and Metabolic Genetics Section, Department of Pediatrics, Hamad Medical Corporation, PO Box 3050, Doha, Qatar; Weill Cornell Medical College, Qatar, Education City, PO Box 24144, Doha, Qatar.
authors: Mariam
authors: M
authors: Almuriekhi
authors: Department of Medical Genetics, School of Medicine, Istanbul Bilim University, Istanbul 34394, Turkey.
authors: Ahmet Okay
authors: AO
authors: Çağlayan
authors: Division of Neurology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors: Jiri
authors: J
authors: Vajsar
authors: Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, School of Medicine, Yale University, New Haven, CT 06510, USA.
authors: Kaya
authors: K
authors: Bilgüvar
authors: Department of Genetics, School of Medicine, Ondokuz Mayis University, 55000 Samsun, Turkey.
authors: Gonul
authors: G
authors: Ogur
authors: Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Philipp-Rosenthal-Str. 55, 04103 Leipzig, Germany; Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors: Rami
authors: R
authors: Abou Jamra
authors: Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, School of Medicine, Yale University, New Haven, CT 06510, USA.
authors: Murat
authors: M
authors: Günel
authors: Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA. Electronic address: jogleeson@mail.rockefeller.edu.
authors: Joseph G
authors: JG
authors: Gleeson
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001485:Basement Membrane / Q000378:metabolism; D001921:Brain / Q000002:abnormalities / Q000000981:diagnostic imaging; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002531:Cerebellum / Q000002:abnormalities / Q000000981:diagnostic imaging; D054222:Cobblestone Lissencephaly / Q000000981:diagnostic imaging / Q000235:genetics*; D002658:Developmental Disabilities / Q000000981:diagnostic imaging / Q000235:genetics; D049030:Dystroglycans / Q000378:metabolism; D005124:Eye Abnormalities / Q000000981:diagnostic imaging / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009421:Nervous System Malformations / Q000000981:diagnostic imaging / Q000235:genetics; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000473:pathology; D010375:Pedigree; D010641:Phenotype
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C561874:TMTC3 protein, human; D049030:Dystroglycans
keywords: TMTC3; alpha-dystroglycan; cobblestone lissencephaly; endoplasmic reticulum