ARX – Corpus Callosum Agenesis–Abnormal Genitalia Syndrome

ARX (HGNC:18060) is an X-linked aristaless-related homeobox transcription factor whose mutations underlie a broad spectrum of neurodevelopmental disorders. Among these, Corpus Callosum Agenesis–Abnormal Genitalia Syndrome is characterized by agenesis of the corpus callosum, genital anomalies, intellectual disability, developmental delay, and early-onset epileptic encephalopathy.

Early multi-patient studies identified close to 100 families and isolated cases harboring 44 distinct ARX mutations, the majority being polyalanine tract expansions, across at least ten clinical entities including corpus callosum agenesis–abnormal genitalia syndrome (PMID:20506206).

A recent Korean family report described a novel heterozygous truncating variant, c.1153A>T (p.Lys385Ter), segregating with intellectual disability, developmental delay, agenesis of the corpus callosum, and developmental epileptic encephalopathy in a proband and three affected female relatives across three generations (PMID:39408661).

ARX variant spectrum includes polyalanine expansions (e.g., c.428_451dup24), homeodomain missense changes, and protein-truncating alleles. The c.1153A>T (p.Lys385Ter) variant predicts a loss-of-function effect and is the first report of a maternally inherited dominant truncation associated with corpus callosum agenesis and encephalopathy (PMID:39408661).

Functional assays demonstrate that ARX is a potent Groucho/TLE-dependent transcriptional repressor modulated by its octapeptide and polyalanine domains; naturally occurring truncating and homeodomain mutations abolish nuclear import and repression activity in vitro (PMID:17331656; PMID:20148114). Mouse Arx null and point-mutation models recapitulate forebrain interneuron and structural defects concordant with corpus callosum agenesis (PMID:20148114).

Taken together, the genetic and experimental concordance supports a strong clinical validity for ARX in corpus callosum agenesis–abnormal genitalia syndrome. Loss-of-function mutations in ARX disrupt transcriptional repression necessary for forebrain development. Key take-home: ARX mutation screening, including truncating alleles, is crucial for the diagnosis and genetic counseling of patients with agenesis of the corpus callosum and related genital anomalies.

References

• Human mutation • 2010 • ARX spectrum disorders: making inroads into the molecular pathology. PMID:20506206
• International journal of molecular sciences • 2024 • The Aggravation of Neuropsychiatric Symptoms in the Offspring of a Korean Family with Intellectual Disability and Developmental Delay Caused by a Novel ARX p.Lys385Ter Variant. PMID:39408661
• 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
• PathoGenetics • 2010 • Mutations in the nuclear localization sequence of the Aristaless related homeobox; sequestration of mutant ARX with IPO13 disrupts normal subcellular distribution of the transcription factor and retards cell division. PMID:20148114
• Biochemical and biophysical research communications • 2008 • The function of the Aristaless-related homeobox (Arx) gene product as a transcriptional repressor is diminished by mutations associated with X-linked mental retardation (XLMR). PMID:18835247

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