PMID- 14722918 OWN - NLM STAT- MEDLINE DCOM- 20040308 LR - 20211230 IS - 1098-1004 (Electronic) IS - 1059-7794 (Linking) VI - 23 IP - 2 DP - 2004 Feb TI - Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. PG - 147-159 LID - 10.1002/humu.10310 [doi] AB - 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. CI - Copyright 2003 Wiley-Liss, Inc. FAU - Kato, Mitsuhiro AU - Kato M AD - Department of Human Genetics, The University of Chicago, Chicago, Illinois. AD - Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan. FAU - Das, Soma AU - Das S AD - Department of Human Genetics, The University of Chicago, Chicago, Illinois. FAU - Petras, Kristin AU - Petras K AD - Department of Human Genetics, The University of Chicago, Chicago, Illinois. FAU - Kitamura, Kunio AU - Kitamura K AD - Mitsubishi Kagaku Institute of Life Sciences, Tokyo, Japan. FAU - Morohashi, Ken-Ichirou AU - Morohashi KI AD - Department of Developmental Biology, National Institute for Basic Biology, Okazaki, Japan. FAU - Abuelo, Diane N AU - Abuelo DN AD - Department of Pediatrics, Rhode Island Hospital, Providence, Rhode Island. FAU - Barr, Mason AU - Barr M AD - Teratology Unit, Departments of Pediatrics, Pathology, and Obstetrics, University of Michigan, Ann Arbor, Michigan. FAU - Bonneau, Dominique AU - Bonneau D AD - Service de Genetique Medicale, Centre Hospitalier Universitaire d'Angers, Angers, France. FAU - Brady, Angela F AU - Brady AF AD - North West Thames Regional Genetics Service, Kennedy-Galton Centre, North West London Hospitals NHS Trust, London, UK. FAU - Carpenter, Nancy J AU - Carpenter NJ AD - HA Chapman Institute of Medical Genetics, University of Oklahoma Health Science Center, Tulsa, Oklahoma. FAU - Cipero, Karen L AU - Cipero KL AD - Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania. FAU - Frisone, Francesco AU - Frisone F AD - Congregazione Suore Infermiere dell'Addolorata, Ospedale Generale di Zona "Valduce", Divisione di Patologia Neonatale, Como, Italy. FAU - Fukuda, Takayuki AU - Fukuda T AD - Department of Developmental Biology, National Institute for Basic Biology, Okazaki, Japan. FAU - Guerrini, Renzo AU - Guerrini R AD - INPE Istituto di Neuropsichiatria e Psicopedagogia dellieta evolutiva, Universita degli Studi di Pisa-IRCCS Stella Maris, Pisa, Italy. FAU - Iida, Eri AU - Iida E AD - Mitsubishi Kagaku Institute of Life Sciences, Tokyo, Japan. FAU - Itoh, Masayuki AU - Itoh M AD - National Center of Neurology and Psychiatry, National Institute of Neuroscience, Tokyo, Japan. FAU - Lewanda, Amy Feldman AU - Lewanda AF AD - Division of Genetics, Inova Fairfax Hospital for Children, Falls Church, Virginia. AD - Johns Hopkins University School of Medicine, Baltimore, Maryland. FAU - Nanba, Yukiko AU - Nanba Y AD - Tottori University School of Medicine, Yonago, Japan. FAU - Oka, Akira AU - Oka A AD - Tottori University School of Medicine, Yonago, Japan. FAU - Proud, Virginia K AU - Proud VK AD - Department of Pediatrics (Medical Genetics), Eastern Virginia Medical School; Norfolk, Virginia. FAU - Saugier-Veber, Pascale AU - Saugier-Veber P AD - Service de Medecine Neonatale et Service de Genetique, Centre Hospitalier Universitaire de Rouen, Rouen, France. FAU - Schelley, Susan L AU - Schelley SL AD - Department of Pediatrics (Genetics), Stanford University, Stanford, California. FAU - Selicorni, Angelo AU - Selicorni A AD - Centro di Genetica Clinica per l'Infanzia, I Clinica Pediatrica Universita di Milano, Milan, Italy. FAU - Shaner, Rachel AU - Shaner R AD - Department of Pediatrics, Rhode Island Hospital, Providence, Rhode Island. FAU - Silengo, Margherita AU - Silengo M AD - Department of Pediatrics, University of Torino, Torino, Italy. FAU - Stewart, Fiona AU - Stewart F AD - Department of Medical Genetics, Belfast City Hospital, Belfast, UK. FAU - Sugiyama, Noriyuki AU - Sugiyama N AD - Department of Developmental Biology, National Institute for Basic Biology, Okazaki, Japan. FAU - Toyama, Jun AU - Toyama J AD - Department of Pediatrics, Okinawa Child Development Center, Okinawa, Japan. FAU - Toutain, Annick AU - Toutain A AD - Service de Genetique et Service de Neuropediatrie, Centre Hospitalier Universitaire de Tours, Tours, France. FAU - Vargas, Ana Lia AU - Vargas AL AD - Instituto de Genetica; Universidad Nacional de Cuyo, Mendoza, Argentina. FAU - Yanazawa, Masako AU - Yanazawa M AD - Mitsubishi Kagaku Institute of Life Sciences, Tokyo, Japan. FAU - Zackai, Elaine H AU - Zackai EH AD - Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania. FAU - Dobyns, William B AU - Dobyns WB AD - Department of Human Genetics, The University of Chicago, Chicago, Illinois. LA - eng GR - P01 NS39404/NS/NINDS NIH HHS/United States PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Hum Mutat JT - Human mutation JID - 9215429 RN - 0 (ARX protein, human) RN - 0 (Homeodomain Proteins) RN - 0 (Transcription Factors) SB - IM MH - Abnormalities, Multiple/genetics/pathology MH - Agenesis of Corpus Callosum MH - Cells, Cultured MH - Corpus Callosum/pathology MH - DNA Mutational Analysis/methods MH - Female MH - Gene Expression Regulation/*genetics MH - Genetic Linkage/genetics MH - Genitalia, Female/abnormalities/pathology MH - Genitalia, Male/abnormalities/pathology MH - Genotype MH - Homeodomain Proteins/biosynthesis/*genetics MH - Humans MH - Infant, Newborn MH - Lymphocytes/chemistry/metabolism/pathology MH - Magnetic Resonance Imaging MH - Male MH - Mutation/*genetics MH - Mutation, Missense/genetics MH - Pedigree MH - Phenotype MH - Sex Chromosome Disorders/genetics MH - Transcription Factors/biosynthesis/*genetics EDAT- 2004/01/15 05:00 MHDA- 2004/03/09 05:00 CRDT- 2004/01/15 05:00 PHST- 2004/01/15 05:00 [pubmed] PHST- 2004/03/09 05:00 [medline] PHST- 2004/01/15 05:00 [entrez] AID - 10.1002/humu.10310 [doi] PST - ppublish SO - Hum Mutat. 2004 Feb;23(2):147-159. doi: 10.1002/humu.10310.