Mutations of ARX Are Associated with Striking Pleiotropy and Consistent Genotype-Phenotype Correlation

Mitsuhiro Kato, Soma Das, Kristin Petras, Kunio Kitamura, Ken Ichirou Morohashi, Diane N. Abuelo, Mason Barr, Dominique Bonneau, Angela F. Brady, Nancy J. Carpenter, Karen L. Cipero, Francesco Frisone, Takayuki Fukuda, Renzo Guerrini, Eri Iida, Masayuki Itoh, Amy Feldman Lewanda, Yukiko Nanba, Akira Oka, Virginia K. ProudPascale Saugier-Veber, Susan L. Schelley, Angelo Selicorni, Rachel Shaner, Margherita Silengo, Fiona Stewart, Noriyuki Sugiyama, Jun Toyama, Annick Toutain, Ana Lía Vargas, Masako Yanazawa, Elaine H. Zackai, William B. Dobyns

Research output: Contribution to journalReview article

237 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)147-159
Number of pages13
JournalHuman mutation
Volume23
Issue number2
DOIs
Publication statusPublished - Feb 23 2004
Externally publishedYes

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Classical Lissencephalies and Subcortical Band Heterotopias
Genetic Association Studies
Genitalia
Mutation
Missense Mutation
Infantile Spasms
Phenotype
Intellectual Disability
Exons
Hydranencephaly
Agenesis of Corpus Callosum
Microcephaly
Frameshift Mutation
Dystonia
Nonsense Codon
Homeobox Genes
Autistic Disorder
Seizures
Nucleotides
Brain

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Mutations of ARX Are Associated with Striking Pleiotropy and Consistent Genotype-Phenotype Correlation. / Kato, Mitsuhiro; Das, Soma; Petras, Kristin; Kitamura, Kunio; Morohashi, Ken Ichirou; Abuelo, Diane N.; Barr, Mason; Bonneau, Dominique; Brady, Angela F.; Carpenter, Nancy J.; Cipero, Karen L.; Frisone, Francesco; Fukuda, Takayuki; Guerrini, Renzo; Iida, Eri; Itoh, Masayuki; Lewanda, Amy Feldman; Nanba, Yukiko; Oka, Akira; Proud, Virginia K.; Saugier-Veber, Pascale; Schelley, Susan L.; Selicorni, Angelo; Shaner, Rachel; Silengo, Margherita; Stewart, Fiona; Sugiyama, Noriyuki; Toyama, Jun; Toutain, Annick; Vargas, Ana Lía; Yanazawa, Masako; Zackai, Elaine H.; Dobyns, William B.

In: Human mutation, Vol. 23, No. 2, 23.02.2004, p. 147-159.

Research output: Contribution to journalReview article

Kato, M, Das, S, Petras, K, Kitamura, K, Morohashi, KI, Abuelo, DN, Barr, M, Bonneau, D, Brady, AF, Carpenter, NJ, Cipero, KL, Frisone, F, Fukuda, T, Guerrini, R, Iida, E, Itoh, M, Lewanda, AF, Nanba, Y, Oka, A, Proud, VK, Saugier-Veber, P, Schelley, SL, Selicorni, A, Shaner, R, Silengo, M, Stewart, F, Sugiyama, N, Toyama, J, Toutain, A, Vargas, AL, Yanazawa, M, Zackai, EH & Dobyns, WB 2004, 'Mutations of ARX Are Associated with Striking Pleiotropy and Consistent Genotype-Phenotype Correlation', Human mutation, vol. 23, no. 2, pp. 147-159. https://doi.org/10.1002/humu.10310
Kato, Mitsuhiro ; Das, Soma ; Petras, Kristin ; Kitamura, Kunio ; Morohashi, Ken Ichirou ; Abuelo, Diane N. ; Barr, Mason ; Bonneau, Dominique ; Brady, Angela F. ; Carpenter, Nancy J. ; Cipero, Karen L. ; Frisone, Francesco ; Fukuda, Takayuki ; Guerrini, Renzo ; Iida, Eri ; Itoh, Masayuki ; Lewanda, Amy Feldman ; Nanba, Yukiko ; Oka, Akira ; Proud, Virginia K. ; Saugier-Veber, Pascale ; Schelley, Susan L. ; Selicorni, Angelo ; Shaner, Rachel ; Silengo, Margherita ; Stewart, Fiona ; Sugiyama, Noriyuki ; Toyama, Jun ; Toutain, Annick ; Vargas, Ana Lía ; Yanazawa, Masako ; Zackai, Elaine H. ; Dobyns, William B. / Mutations of ARX Are Associated with Striking Pleiotropy and Consistent Genotype-Phenotype Correlation. In: Human mutation. 2004 ; Vol. 23, No. 2. pp. 147-159.
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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.",
author = "Mitsuhiro Kato and Soma Das and Kristin Petras and Kunio Kitamura and Morohashi, {Ken Ichirou} and Abuelo, {Diane N.} and Mason Barr and Dominique Bonneau and Brady, {Angela F.} and Carpenter, {Nancy J.} and Cipero, {Karen L.} and Francesco Frisone and Takayuki Fukuda and Renzo Guerrini and Eri Iida and Masayuki Itoh and Lewanda, {Amy Feldman} and Yukiko Nanba and Akira Oka and Proud, {Virginia K.} and Pascale Saugier-Veber and Schelley, {Susan L.} and Angelo Selicorni and Rachel Shaner and Margherita Silengo and Fiona Stewart and Noriyuki Sugiyama and Jun Toyama and Annick Toutain and Vargas, {Ana L{\'i}a} and Masako Yanazawa and Zackai, {Elaine H.} and Dobyns, {William B.}",
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T1 - Mutations of ARX Are Associated with Striking Pleiotropy and Consistent Genotype-Phenotype Correlation

AU - Kato, Mitsuhiro

AU - Das, Soma

AU - Petras, Kristin

AU - Kitamura, Kunio

AU - Morohashi, Ken Ichirou

AU - Abuelo, Diane N.

AU - Barr, Mason

AU - Bonneau, Dominique

AU - Brady, Angela F.

AU - Carpenter, Nancy J.

AU - Cipero, Karen L.

AU - Frisone, Francesco

AU - Fukuda, Takayuki

AU - Guerrini, Renzo

AU - Iida, Eri

AU - Itoh, Masayuki

AU - Lewanda, Amy Feldman

AU - Nanba, Yukiko

AU - Oka, Akira

AU - Proud, Virginia K.

AU - Saugier-Veber, Pascale

AU - Schelley, Susan L.

AU - Selicorni, Angelo

AU - Shaner, Rachel

AU - Silengo, Margherita

AU - Stewart, Fiona

AU - Sugiyama, Noriyuki

AU - Toyama, Jun

AU - Toutain, Annick

AU - Vargas, Ana Lía

AU - Yanazawa, Masako

AU - Zackai, Elaine H.

AU - Dobyns, William B.

PY - 2004/2/23

Y1 - 2004/2/23

N2 - 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.

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.

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