ARX: a gene for all seasons

Inspired by a patient

Gécz J, Cloosterman D, Partington M. ARX: a gene for all seasons. Curr Opin Genet Dev. 2006 Jun;16(3):308-16. doi: 10.1016/j.gde.2006.04.003. Epub 2006 May 2. PMID: 16650978.

Abstract

The Aristaless-related homeobox gene, ARX, is an important transcription factor with a crucial role in forebrain, pancreas and testes development. At least fifty-nine mutations have been described in the ARX gene in seven X-chromosome linked disorders involving mental retardation. Recent studies with ARX screening suggest that the gene is mutated in 9.5% of X-linked families with these disorders. Two different polyalanine expansion mutations represent 46% of all currently known mutations and show considerable pleiotropy. The ARX gene is emerging as one of the more important disease-causing genes on the X chromosome and ought to be considered for routine screening. Although the normal Arx protein is known to be a bifunctional transcriptional activator and repressor, the complete biochemical characterization of the normal and mutated ARX awaits further investigation. Pax4 was identified as one of the ARX target genes, and both proteins have crucial functions in endocrine mouse pancreas alpha-cell and beta-cell lineage specification.

Lisik M, Sieroń AL. ARX--jeden gen--wiele postaci niepełnosprawności intelektualnej [ARX--one gene--many phenotypes]. Neurol Neurochir Pol. 2008 Jul-Aug;42(4):338-44. Polish. PMID: 18975239.

Abstract

Mental retardation is a serious social problem. It affects 2-3% of the population. It is estimated that mutations in the ARX gene can be found in 1 in 12,000 live male births. This is the second most common cause of X-linked mental retardation after fragile X syndrome. The ARX gene belongs to transcription factors involved in differentiation of specific neuronal cells in the central nervous system. The most common mutation in the ARX gene is c. 428_451dup24, duplication of 24 bp in exon 2 of the gene, causing elongation of the second alanine tract (polyA12_II). Described disorders caused by mutations in the ARX gene include: hydrocephaly with abnormal genitalia (HYD-AG), lissencephaly with abnormal genitalia (XLAG), agenesis of corpus callosum with abnormal genitalia (ACC-AG), Partington syndrome (PRTS), X-linked infantile spasms (ISSX), myoclonic epilepsy with spasticity and mental retardation (XMESID), and nonspecific mental retardation (NS-XLMR).

Takeshita Y, Ohto T, Enokizono T, Tanaka M, Suzuki H, Fukushima H, Uehara T, Takenouchi T, Kosaki K, Takada H. Novel ARX mutation identified in infantile spasm syndrome patient. Hum Genome Var. 2020 Mar 31;7:9. doi: 10.1038/s41439-020-0094-2. PMID: 32257294; PMCID: PMC7109071.

Abstract

We report a 7-year-old boy with infantile spasms caused by a novel mutation in the Aristaless-related homeobox (ARX) gene. He showed infantile spasms and hypsarrhythmia on electroencephalogram from early infancy. Brain MRI did not reveal severe malformation of the brain except mild hypoplasia of the corpus callosum. Two-fold adrenocorticotropic hormone (ACTH) therapy failed to control the seizures, and ketogenic diet therapy and multi-antiepileptic drug therapy were required as he showed intractable daily tonic-clonic seizures. Exome sequencing identified a hemizygous mutation in the ARX gene, NG_008281.1(ARX_v001):c.1448 + 1 G > A, chrX: 25025227 C > T (GRCh37). To our knowledge, this mutation has not been reported previously.