Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.

SUMMARY Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function.

Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous families with autism, epilepsy, and intellectual disability. The encoded protein is responsible for phosphorylation-mediated inactivation of the E1α subunit of branched-chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1α phosphorylation, and plasma branched-chain amino acids. Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome.

Loss of the endosomal anion transport protein ClC-5 impairs renal endocytosis and underlies human Dent's disease. ClC-5 is thought to promote endocytosis by facilitating endosomal acidification through the neutralization of proton pump currents. However, ClC-5 is a 2 chloride (Cl-)/proton (H+) exchanger rather than a Cl- channel. We generated mice that carry the uncoupling E211A (unc) mutation that converts ClC-5 into a pure Cl- conductor. Adenosine triphosphate (ATP)-dependent acidification of renal endosomes was reduced in mice in which ClC-5 was knocked out, but normal in Clcn5(unc) mice. However, their proximal tubular endocytosis was also impaired. Thus, endosomal chloride concentration, which is raised by ClC-5 in exchange for protons accumulated by the H+-ATPase, may play a role in endocytosis.

Exome sequencing of 118 patients with neurodevelopmental disorders shows that this technique is useful for identifying new pathogenic mutations and for correcting diagnosis in ~10% of cases.

Trends in Neurosciences diagnoses. We also highlight the relevance of the two-hit model in the context of understanding the genetics of NDDs. Finally, we debate whether the identification of frequently affected cellular pathways allows circumventing the issue of the wide genetic variability of NDDs and whether the identification of such pathways could open perspectives for future treatments.

No abstract

No abstract