ARX – X-linked lissencephaly with abnormal genitalia

ARX (HGNC:18060) encodes a paired-type homeobox transcription factor essential for forebrain development. Hemizygous loss-of-function mutations in ARX lead to X-linked lissencephaly with abnormal genitalia (MONDO:0010268), an X-linked recessive syndrome characterized by agyria or pachygyria, agenesis of the corpus callosum, ambiguous genitalia, and refractory seizures.

Genetic evidence includes 20 unrelated hemizygous males from 16 families with frameshift, nonsense, splice site, and polyalanine expansion ARX variants segregating with disease (PMID:14722918). Familial segregation and absence of these variants in unaffected carriers support pathogenicity under an X-linked recessive model.

Case reports detail a 1-bp deletion c.790del (p.Arg264fs) resulting in prolonged survival with novel pancreatic insufficiency and renal phosphate wasting (PMID:15248105), and a familial c.1384_1406del (p.Leu462fs) in two male infants with agenesis of the corpus callosum and intractable epilepsy (PMID:15248097).

The variant spectrum encompasses loss-of-function mutations in exons 1–4 (large deletions, frameshifts, nonsense, splice donors), recurrent polyalanine tract expansions (e.g., c.428_451dup24), and missense mutations in the homeodomain. Genotype-phenotype correlations show more severe malformations with truncating and homeodomain variants.

Functional studies demonstrate that ARX mutations abolish DNA binding and transcriptional repression through disrupted interaction with Groucho/TLE cofactors and impaired nuclear localization (PMID:22194193, PMID:17331656). Arx-null and knock-in mouse models recapitulate cortical interneuron deficits, hypothalamic dysfunction, and epilepsy phenotypes.

Key take-home: Definitive evidence supports ARX mutational analysis in males presenting with lissencephaly, agenesis of the corpus callosum, ambiguous genitalia, and early-onset seizures.

References

• Neuropediatrics • 2004 • X-linked lissencephaly with abnormal genitalia associated with renal phosphate wasting. PMID:15248105
• Neuropediatrics • 2004 • Agenesis of the corpus callosum, abnormal genitalia and intractable epilepsy due to a novel familial mutation in the Aristaless-related homeobox gene. PMID:15248097
• Human mutation • 2004 • Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. PMID:14722918
• Human molecular genetics • 2012 • ARX homeodomain mutations abolish DNA binding and lead to a loss of transcriptional repression. PMID:22194193
• Neuroscience • 2007 • Aristaless-related homeobox gene, the gene responsible for West syndrome and related disorders, is a Groucho/transducin-like enhancer of split dependent transcriptional repressor. PMID:17331656

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