RESUMEN
RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.
Asunto(s)
Trastorno Autístico/genética , Ataxia Cerebelosa/genética , Genes Dominantes , Discapacidad Intelectual/genética , Mutación Missense/genética , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Adolescente , Adulto , Anciano de 80 o más Años , Alelos , Animales , Trastorno Autístico/complicaciones , Encéfalo/patología , Ataxia Cerebelosa/complicaciones , Niño , Preescolar , Variaciones en el Número de Copia de ADN/genética , Modelos Animales de Enfermedad , Femenino , Prueba de Complementación Genética , Humanos , Discapacidad Intelectual/complicaciones , Larva/genética , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Células de Purkinje/metabolismo , Células de Purkinje/patología , Síndrome , Pez Cebra/genéticaRESUMEN
Peroxisomes play an essential role in lipid metabolism via interaction with other intracellular organelles. The information about the role of the Acyl-CoA-binding domain containing-protein 5 (ACBD5) in these interactions in human cells is emerging. Moreover, a few patients with retinal dystrophy and leukodystrophy caused by pathogenic variants in ACBD5 have been recently introduced. Here, we present a 36-year-old female with retinal dystrophy, leukodystrophy, and psychomotor regression due to a novel homozygous variant in ACBD5. Our study adds to the growing knowledge of this peroxisomal disorder by providing phenotypic details of the first adult patient.