title: Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation.
abstract: We recently identified mutations of ARX in nine genotypic males with X-linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia. We obtained detailed clinical information on all 29 affected males, including the nine previously reported subjects. Premature termination mutations consisting of large deletions, frameshifts, nonsense mutations, and splice site mutations in exons 1 to 4 caused XLAG or hydranencephaly with abnormal genitalia. Nonconservative missense mutations within the homeobox caused less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome. A nonconservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. In addition, several less severe phenotypes without malformations have been reported, including mental retardation with cryptogenic infantile spasms (West syndrome), other seizure types, dystonia or autism, and nonsyndromic mental retardation. The ARX mutations associated with these phenotypes have included polyalanine expansions or duplications, missense mutations, and one deletion of exon 5. Together, the group of phenotypes associated with ARX mutations demonstrates remarkable pleiotropy, but also comprises a nearly continuous series of developmental disorders that begins with hydranencephaly, lissencephaly, and agenesis of the corpus callosum, and ends with a series of overlapping syndromes with apparently normal brain structure.
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois.|Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois.
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois.
authors.forename: Kristin
authors.initials: K
authors.lastname: Petras
authors.affiliation: Mitsubishi Kagaku Institute of Life Sciences, Tokyo, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Kitamura
authors.affiliation: Department of Developmental Biology, National Institute for Basic Biology, Okazaki, Japan.
authors.forename: Ken-Ichirou
authors.initials: KI
authors.lastname: Morohashi
authors.affiliation: Department of Pediatrics, Rhode Island Hospital, Providence, Rhode Island.
authors.forename: Diane N
authors.initials: DN
authors.lastname: Abuelo
authors.affiliation: Teratology Unit, Departments of Pediatrics, Pathology, and Obstetrics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Mason
authors.initials: M
authors.lastname: Barr
authors.affiliation: Service de Génétique Médicale, Centre Hospitalier Universitaire d'Angers, Angers, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.affiliation: North West Thames Regional Genetics Service, Kennedy-Galton Centre, North West London Hospitals NHS Trust, London, UK.
authors.forename: Angela F
authors.initials: AF
authors.lastname: Brady
authors.affiliation: HA Chapman Institute of Medical Genetics, University of Oklahoma Health Science Center, Tulsa, Oklahoma.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Carpenter
authors.affiliation: Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Cipero
authors.affiliation: Congregazione Suore Infermiere dell'Addolorata, Ospedale Generale di Zona "Valduce", Divisione di Patologia Neonatale, Como, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Frisone
authors.affiliation: Department of Developmental Biology, National Institute for Basic Biology, Okazaki, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: INPE Istituto di Neuropsichiatria e Psicopedagogia dellíeta evolutiva, Universita degli Studi di Pisa-IRCCS Stella Maris, Pisa, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.affiliation: Mitsubishi Kagaku Institute of Life Sciences, Tokyo, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Iida
authors.affiliation: National Center of Neurology and Psychiatry, National Institute of Neuroscience, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Itoh
authors.affiliation: Division of Genetics, Inova Fairfax Hospital for Children, Falls Church, Virginia.|Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Amy Feldman
authors.initials: AF
authors.lastname: Lewanda
authors.affiliation: Tottori University School of Medicine, Yonago, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nanba
authors.affiliation: Tottori University School of Medicine, Yonago, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Oka
authors.affiliation: Department of Pediatrics (Medical Genetics), Eastern Virginia Medical School; Norfolk, Virginia.
authors.forename: Virginia K
authors.initials: VK
authors.lastname: Proud
authors.affiliation: Service de Médecine Néonatale et Service de Génétique, Centre Hospitalier Universitaire de Rouen, Rouen, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Saugier-Veber
authors.affiliation: Department of Pediatrics (Genetics), Stanford University, Stanford, California.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Schelley
authors.affiliation: Centro di Genetica Clinica per l'Infanzia, I Clinica Pediatrica Università di Milano, Milan, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.affiliation: Department of Pediatrics, Rhode Island Hospital, Providence, Rhode Island.
authors.forename: Rachel
authors.initials: R
authors.lastname: Shaner
authors.affiliation: Department of Pediatrics, University of Torino, Torino, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Silengo
authors.affiliation: Department of Medical Genetics, Belfast City Hospital, Belfast, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Stewart
authors.affiliation: Department of Developmental Biology, National Institute for Basic Biology, Okazaki, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sugiyama
authors.affiliation: Department of Pediatrics, Okinawa Child Development Center, Okinawa, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Toyama
authors.affiliation: Service de Génétique et Service de Neuropédiatrie, Centre Hospitalier Universitaire de Tours, Tours, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Toutain
authors.affiliation: Instituto de Genética; Universidad Nacional de Cuyo, Mendoza, Argentina.
authors.forename: Ana Lía
authors.initials: AL
authors.lastname: Vargas
authors.affiliation: Mitsubishi Kagaku Institute of Life Sciences, Tokyo, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Yanazawa
authors.affiliation: Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Elaine H
authors.initials: EH
authors.lastname: Zackai
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois.
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D061085:Agenesis of Corpus Callosum; D002478:Cells, Cultured; D003337:Corpus Callosum / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics; D005836:Genitalia, Female / Q000002:abnormalities / Q000473:pathology; D005837:Genitalia, Male / Q000002:abnormalities / Q000473:pathology; D005838:Genotype; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008214:Lymphocytes / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D025064:Sex Chromosome Disorders / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C469264:ARX protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors