RESUMEN
Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes.
Asunto(s)
Trastornos del Neurodesarrollo , Proteínas de Unión al GTP rac , Animales , Humanos , Ratones , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/metabolismo , Neuronas/metabolismo , Fenotipo , Quinasas p21 Activadas/genética , Proteínas de Unión al GTP rac/genética , Proteínas de Unión al GTP rac/metabolismoRESUMEN
The prevalent form of ichthyosis in neutral lipid storage disease (NLSDI) is nonbullous congenital ichthyosiform erythroderma (CIE) characterized by fine, whitish scales on erythematous skin over the whole body. Here, we report a late-diagnosed, 25-year-old woman with NLSDI presenting with diffuse erythema and fine whitish scales throughout the body with patches of apparently normal skin, "islets of sparing" on her lower extremities. We observed that the size of the normal skin islets changed with time, and even the entire lower extremity was covered with erythema and desquamation like the rest of the body. Frozen section histopathological examinations were made from lesional skin and normal-looking skin; no difference was observed in terms of lipid accumulation. The only noticeable difference was the thickness of the keratin layer. In CIE patients, observation of patches of apparently normal skin or "islets of sparing" might be a clue for NLSDI to be distinguished from other CIE conditions.