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Eur J Med Genet ; : 103777, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31580924


Snyder-Robinson syndrome (SRS) is an X-linked syndromic intellectual disability condition caused by variants in the spermine synthase gene (SMS). The syndrome is characterized by facial dysmorphism, thin body build, kyphoscoliosis, osteoporosis, hypotonia, developmental delay and associated neurological features (seizures, unsteady gait, abnormal speech). Until now, only missense variants with a functionally characterized partial loss of function (LoF) have been described. Here we describe the first complete LoF variant, Met303Lysfs*, in a male patient with a severe form of Snyder-Robinson syndrome. He presented with multiple malformations and severly delayed development, and died at 4 months of age. Functional in vitro assays showed a complete absence of functional SMS protein. Taken together, our findings and those of previously reported patients confirm that pathogenic variants of SMS are indeed LoF and that there might exist a genotype-phenotype correlation between the type of variant and the severity of the syndrome.

J Clin Invest ; 129(5): 2145-2162, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30985297


Vacuolar H+-ATPase-dependent (V-ATPase-dependent) functions are critical for neural proteostasis and are involved in neurodegeneration and brain tumorigenesis. We identified a patient with fulminant neurodegeneration of the developing brain carrying a de novo splice site variant in ATP6AP2 encoding an accessory protein of the V-ATPase. Functional studies of induced pluripotent stem cell-derived (iPSC-derived) neurons from this patient revealed reduced spontaneous activity and severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death. These deficiencies could be rescued by expression of full-length ATP6AP2. Conditional deletion of Atp6ap2 in developing mouse brain impaired V-ATPase-dependent functions, causing impaired neural stem cell self-renewal, premature neuronal differentiation, and apoptosis resulting in degeneration of nearly the entire cortex. In vitro studies revealed that ATP6AP2 deficiency decreases V-ATPase membrane assembly and increases endosomal-lysosomal fusion. We conclude that ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation in the developing human central nervous system.

Brain ; 133(Pt 5): 1391-402, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20395263


We have studied a family with severe mental retardation characterized by the virtual absence of speech, autism spectrum disorder, epilepsy, late-onset ataxia, weakness and dystonia. Post-mortem examination of two males revealed widespread neuronal loss, with the most striking finding being neuronal and glial tau deposition in a pattern reminiscent of corticobasal degeneration. Electron microscopic examination of isolated tau filaments demonstrated paired helical filaments and ribbon-like structures. Biochemical studies of tau demonstrated a preponderance of 4R tau isoforms. The phenotype was linked to Xq26.3, and further analysis identified an in-frame 9 base pair deletion in the solute carrier family 9, isoform A6 (SLC9A6 gene), which encodes sodium/hydrogen exchanger-6 localized to endosomal vesicles. Sodium/hydrogen exchanger-6 is thought to participate in the targeting of intracellular vesicles and may be involved in recycling synaptic vesicles. The striking tau deposition in our subjects reveals a probable interaction between sodium/proton exchangers and cytoskeletal elements involved in vesicular transport, and raises the possibility that abnormalities of vesicular targeting may play an important role in more common disorders such as Alzheimer's disease and autism spectrum disorders.

Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Mutação , Trocadores de Sódio-Hidrogênio/genética , Proteínas tau/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Pré-Escolar , Deleção de Genes , Ligação Genética , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/psicologia , Masculino , Microscopia Eletrônica , Biologia Molecular/métodos , Neuroglia/metabolismo , Neurônios/metabolismo , Linhagem , Fenótipo , Isoformas de Proteínas/metabolismo , Índice de Gravidade de Doença , Proteínas tau/ultraestrutura