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.

Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X)

“…Interestingly, virtually all of these cause the X-linked lissencephaly with ambiguous genitalia (XLAG) phenotype, which represents the severe malformation end of the phenotypic spectrum of ARX-associated disorders. 9,10 All of these mutations can also be considered ARX null mutations, which is an assumption supported by the original discovery of the human XLAG mutations that mimic the Arx mouse knockout model. 3 We predict that the c.81C4G/ p.Y27X mutation is also akin to a null mutation.…”

Mutational screening of ARX gene in Brazilian males with mental retardation of unknown etiology

“…We did not find this mutation in 14 BP families or in 108 SC. To date, 31 families with the c.428_451dup(24 bp) mutation including those from this report, have been described (Bienvenu et al 2002;Frints et al 2002;Stromme et al 2002;Turner et al 2002;Gronskov et al 2004;Kato et al 2004;Partington et al 2004;van Esch et al 2004;GestinariDuarte et al 2006;Poirier et al 2005Poirier et al , 2006Stepp et al 2005;Nawara et al 2006). …”

“…Although this variant was firstly identified in a boy with XLAG (Kato et al 2004) and in a boy with MR (Gronskov et al 2004), it was also found in 4% of the normal controls tested in these studies. Gronskov et al (2004) performed in-silico analysis through ESEfinder program and showed that c.1347C>T creates a strong binding site for SRp55, a kind of splicing binding factor to exonic splice enhancers (ESE).…”

“…Our results did not shown any significant alterations in the splicing site values compared to the wild-type sequence, which suggests that it is a polymorphism. To date, 11 intronic variants have been reported in the ARX gene, 9 as polymorphisms and 2 have been identified in XLAG individuals, and described as premature stop codon mutations (Kato et al 2004). …”

Reinitiation of mRNA translation in a patient with X-linked infantile spasms with a protein-truncating variant in ARX

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] Other mutations in ARX lead to severe malformations of the brain and genitalia such as Proud syndrome with agenesis of the corpus callosum and abnormal genitalia, 20 hydranencephaly with abnormal genitalia, 20,21 and X-linked lissencephaly with abnormal genitalia (XLAG). 1, [20][21][22][23][24][25][26][27][28] Mutations that lead to severe malformation phenotypes are usually protein truncation and point mutations in critical residues, leading to complete loss-of-function ARX protein.…”