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

University of Milan, Milano, Lombardy, Italy
Human Mutation (Impact Factor: 5.14). 03/2004; 23(2):147-59. DOI: 10.1002/humu.10310
Source: PubMed


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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Available from: Annick Toutain, Feb 06, 2015
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    • "Novel ARX Gene Mutation Sex Dev 2014;8:156–159 DOI: 10.1159/000365458 tellectual disability, agenesis of the corpus callosum, and characteristic facies), and numerous other syndromic and nonsyndromic forms of X-linked mental retardation and autism [Hartmann et al., 2004; Kato et al., 2004]. The striking intra-and interfamilial pleiotropy together with genetic heterogeneity are a hallmark of ARX mutations [Shoubridge et al., 2010]. "
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    ABSTRACT: The objective of this study was to identify disease-causing mutations in a Sri Lankan male child presenting with ambiguous genitalia and psychomotor delay using the exome sequencing approach. A novel mutation in the aristaless-related homeobox (ARX) gene causing a hemizygous nucleotide substitution in exon 5 was identified (NM_139058.2 (ARX): c.1614G>T; p.K538N). This change causes a nonsynonymous substitution in the aristaless domain within the ARX protein which is predicted to be deleterious. This is the first reported case of ambiguous genitalia and psychomotor delay associated with this novel missense mutation within the ARX protein, and it highlights the value of exome sequencing even in sporadic cases. © 2014 S. Karger AG, Basel.
    Full-text · Article · Jul 2014 · Sexual Development
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    • "Analyses using genetically modified mouse models have been performed to explore the impact different ARX mutations have on neuronal development and cognitive functionality; these models demonstrate a similar genotype-phenotype correlation to humans [13]. Specifically, mouse models with an expansion mutation of the first polyalanine tract of Arx reveal that only tangential migration of GABA-ergic interneurons is lost, with no significant impact to radial migration [14], [15]. "
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    ABSTRACT: ARX/Arx is a homeodomain-containing transcription factor necessary for the specification and early maintenance of pancreatic endocrine α-cells. Many transcription factors important to pancreas development, including ARX/Arx, are also crucial for proper brain development. Although null mutations of ARX in human patients result in the severe neurologic syndrome XLAG (X-linked lissencephaly associated with abnormal genitalia), the most common mutation is the expansion of the first polyalanine tract of ARX, which results primarily in the clinical syndrome ISSX (infantile spasms). Mouse models of XLAG, ISSX and other human ARX mutations demonstrate a direct genotype-phenotype correlation in ARX-related neurologic disorders. Furthermore, mouse models utilizing a polyalanine tract expansion mutation have illustrated critical developmental differences between null mutations and expansion mutations in the brain, revealing context-specific defects. Although Arx is known to be required for the specification and early maintenance of pancreatic glucagon-producing α-cells, the consequences of the Arx polyalanine expansion on pancreas development remain unknown. Here we report that mice with an expansion mutation in the first polyalanine tract of Arx exhibit impaired α-cell specification and maintenance, with gradual α-cell loss due to apoptosis. This is in contrast to the re-specification of α-cells into β- and δ-cells that occurs in mice null for Arx. Overall, our analysis of an Arx polyalanine expansion mutation on pancreatic development suggests that impaired α-cell function might also occur in ISSX patients.
    Preview · Article · Nov 2013 · PLoS ONE
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    • "Primers were used to amplify the coding and flanking noncoding regions of CDKL5 and ARX. Optimized conditions were used for the GC-rich exon 2 of the ARX gene, as previously described [27]. The coding regions of the CDKL5 (exons 2-21) and ARX (exons 1-5) genes were targeted for mutation analysis performed by Sanger sequencing using standard methods. "
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    ABSTRACT: Mutations in CDKL5 and ARX are known causes of early-onset epilepsy and severe developmental delay in males and females. Although numerous males with ARX mutations associated with various phenotypes have been reported in the literature, the majority of CDKL5 mutations have been identified in females with a phenotype characterized by early-onset epilepsy, severe global developmental delay, absent speech, and stereotypic hand movements. To date, only 10 males with CDKL5 mutations have been reported. Our retrospective study reports on the clinical, neuroimaging, and molecular findings of 18 males with early-onset epilepsy caused by either CDKL5 or ARX mutations. These 18 patients include eight new males with CDKL5 mutations and 10 with ARX mutations identified through sequence analysis of 266 and 346 males, respectively, at our molecular diagnostic laboratory. Our large dataset therefore expands on the number of reported males with CDKL5 mutations and highlights that aberrations of CDKL5 and ARX combined are an important consideration in the genetic forms of early-onset epilepsy in boys.
    Full-text · Article · May 2013 · Pediatric Neurology
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