Liang-Wang syndrome

Liang-Wang syndrome (OMIM #618729) is a congenital polymalformation syndrome with wide variability in symptoms and severity, though all affected individuals experience some degree of neurological dysfunction. In severe cases, patients present with profound developmental delay, intellectual impairment, absent or limited speech, distinctive craniofacial features, and abnormalities in connective tissue, bones, and blood vessels. Milder cases lack significant dysmorphic features, seizures, and visceral involvement but may show developmental and speech delays, strabismus, or ataxia. Brain imaging findings are also variable, with approximately half of patients exhibiting cerebral and cerebellar atrophy or a thin corpus callosum, while the other half have normal imaging results. More info

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Pathogenic mechanisms

Liang-Wang syndrome is caused by mutations in the KCNMA1 gene, which affect various regions, including the transmembrane domains, pore region, and RCK1 or RCK2 domains. Functional studies in HEK293 cells have shown that these mutations lead to a loss of BK potassium current, with some variants (S351Y, G356R, G375R, and I663V) causing a complete loss of function, while others (P805L and D984N) result in reduced protein expression or decreased channel conductivity. KCNMA1 is crucial for neurotransmitter release and membrane repolarization in neurons, as well as for functions in osteoclasts and smooth muscle, which may explain the syndrome’s diverse clinical features. Evidence suggests that truncating mutations causing haploinsufficiency lead to a different phenotype than missense variants, which may exert a dominant-negative effect by interfering with other subunits and binding proteins.

Available Mouse Models

in development