RESUMEN
BACKGROUND AND AIM: Martin--Probst syndrome (MPS) is a rare X-linked disorder characterised by deafness, cognitive impairment, short stature and distinct craniofacial dysmorphisms, among other features. The authors sought to identify the causative mutation for MPS. METHODS AND RESULTS: Massively parallel sequencing in two affected, related male subjects with MPS identified a RAB40AL (also called RLGP) missense mutation (chrX:102,079,078-102,079,079ACâGA p.D59G; hg18). RAB40AL encodes a small Ras-like GTPase protein with one suppressor of cytokine signalling box. The p.D59G variant is located in a highly conserved region of the GTPase domain between ß-2 and ß-3 strands. Using RT-PCR, the authors show that RAB40AL is expressed in human fetal and adult brain and kidney, and adult lung, heart, liver and skeletal muscle. RAB40AL appears to be a primate innovation, with no orthologues found in mouse, Xenopus or zebrafish. Western analysis and fluorescence microscopy of GFP-tagged RAB40AL constructs from transiently transfected COS7 cells show that the D59G missense change renders RAB40AL unstable and disrupts its cytoplasmic localisation. CONCLUSIONS: This is the first study to show that mutation of RAB40AL is associated with a human disorder. Identification of RAB40AL as the gene mutated in MPS allows for further investigations into the molecular mechanism(s) of RAB40AL and its roles in diverse processes such as cognition, hearing and skeletal development.
Asunto(s)
Enfermedades Genéticas Ligadas al Cromosoma X/genética , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Mutación Missense/genética , Proteínas ras/genética , Proteínas ras/metabolismo , Adulto , Animales , Secuencia de Bases , Western Blotting , Células COS , Chlorocebus aethiops , Análisis Mutacional de ADN , Femenino , Feto/química , Enfermedades Genéticas Ligadas al Cromosoma X/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Masculino , Ratones , Datos de Secuencia Molecular , Especificidad de Órganos , Linaje , Primates , Análisis de Secuencia de ADN , Espectrometría de Fluorescencia , SíndromeRESUMEN
Unilateral spatial neglect (neglect) is a syndrome characterized by perceptual deficits that prevent patients from attending and responding to the side of space and of the body opposite a damaged hemisphere (contralesional side). Neglect also involves motor deficits: patients may be slower to initiate a motor response to targets appearing in the left hemispace, even when using their unaffected arm (directional hypokinesia). Although this impairment is well known, its anatomical correlate has not been established. We tested 52 patients with neglect after right hemisphere stroke, and conducted an anatomical analysis on 29 of them to find the anatomical correlate of directional hypokinesia. We found that patients with directional hypokinesia had a lesion involving the ventral lateral putamen, the claustrum, and the white matter underneath the frontal lobe. Most importantly, none of the patients without directional hypokinesia had a lesion in the same region. The localization of neglect's motor deficits to the basal ganglia establishes interesting homologies with animal data; it also suggests that a relative depletion of dopamine in the nigrostriatal pathway on the same side of the lesion may be an important pathophysiological mechanism potentially amenable to intervention.