A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition

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 disorder

Missense mutations in the copper transporter gene ATP7A cause X-Linked distal hereditary motor neuropathy

Distal hereditary motor neuropathies comprise a clinically and genetically heterogeneous group of disorders. We recently mapped an X-linked form of this condition to chromosome Xq13.1-q21 in two large unrelated families. The region of genetic linkage included ATP7A, which encodes a copper-transporting P-type ATPase mutated in patients with Menkes disease, a severe infantile-onset neurodegenerative condition. We identified two unique ATP7A missense mutations (p.P1386S and p.T994I) in males with distal motor neuropathy in two families. These molecular alterations impact highly conserved amino acids in the carboxyl half of ATP7A and do not directly involve the copper transporter's known critical functional domains. Studies of p.P1386S revealed normal ATP7A mRNA and protein levels, a defect in ATP7A trafficking, and partial rescue of a S. cerevisiae copper transport knockout. Although ATP7A mutations are typically associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome, we demonstrate here that certain missense mutations at this locus can cause a syndrome restricted to progressive distal motor neuropathy without overt signs of systemic copper deficiency. This previously unrecognized genotype-phenotype correlation suggests an important role of the ATP7A copper transporter in motor-neuron maintenance and function

Complex Genomic Rearrangements at the PLP1 Locus Include Triplication and Quadruplication

Submitted by Nuzia Santos ([email protected]) on 2015-12-18T17:33:33Z No. of bitstreams: 1 Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication.pdf: 10586124 bytes, checksum: 81d908113b1816f6f5429908832dd4f3 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2015-12-18T17:42:09Z (GMT) No. of bitstreams: 1 Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication.pdf: 10586124 bytes, checksum: 81d908113b1816f6f5429908832dd4f3 (MD5)Made available in DSpace on 2015-12-18T17:42:09Z (GMT). No. of bitstreams: 1 Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication.pdf: 10586124 bytes, checksum: 81d908113b1816f6f5429908832dd4f3 (MD5) Previous issue date: 2015Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, United States of AmericaBaylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, United States of America/Fundação Oswaldo Cruz. Centro de Pesquisa Rene Rachou. Belo Horizonte, MG, BrasilAlfred I. duPont Hospital for Children. Nemours Biomedical Research. Wilmington, DE, United States of AmericaBaylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, United States of AmericaAlfred I. duPont Hospital for Children. Nemours Biomedical Research. Wilmington, DE, United States of AmericaBaylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, United States of AmericaAlfred I. duPont Hospital for Children. Nemours Biomedical Research. Wilmington, DE, United States of AmericaAlfred I. duPont Hospital for Children. Nemours Biomedical Research. Wilmington, DE, United States of America/Thomas Jefferson University. Jefferson Medical College. Philadelphia, PA, United States of AmericaGeorg August University. University Medical Center Göttingen. Division of Pediatric Neurology. Department of Pediatrics and Adolescent Medicine. Göttingen, GermanyCharles University and Motol University Hospital. 2nd Faculty of Medicine. Department of Pediatric Neurology. DNA Laboratory. Prague, Czech RepublicUniversity of Rochester Medical Center. Rochester, NY, United States of AmericaAlfred I. duPont Hospital for Children. Nemours Biomedical Research. Wilmington, DE, United States of America/Thomas Jefferson University. Jefferson Medical College. Philadelphia, PA, United States of America/University of Delaware.Department of Biological Sciences. Newark, DA, United States of AmericaBaylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, United States of America/Baylor College of Medicine. Department of Pediatrics and Human Genome Sequencing Center. Houston, TX, United States of America/Texas Children ’s Hospital, Houston. TX, United States of AmericaInverted repeats (IRs) can facilitate structural variation as crucibles of genomic rearrangement. Complex duplication—inverted triplication—duplication (DUP-TRP/INV-DUP) rearrangements that contain breakpoint junctions within IRs have been recently associated with both MECP2 duplication syndrome (MIM#300260) and Pelizaeus-Merzbacher disease (PMD, MIM#312080). We investigated 17 unrelated PMD subjects with copy number gains at the PLP1 locus including triplication and quadruplication of specific genomic intervals—16/17 were found to have a DUP-TRP/INV-DUP rearrangement product. An IR distal to PLP1 facilitates DUP-TRP/INV-DUP formation as well as an inversion structural variation found frequently amongst normal individuals. We show that a homology—or homeology—driven replicative mechanism of DNA repair can apparently mediate template switches within stretches of microhomology. Moreover, we provide evidence that quadruplication and potentially higher order amplification of a genomic interval can occur in a manner consistent with rolling circle amplification as predicted by the microhomology-mediated break induced replication (MMBIR

Do Not Trust the Pedigree: Reduced and Sex‐Dependent Penetrance at a Novel Mutation Hotspot in ATL1 Blurs Autosomal Dominant Inheritance of Spastic Paraplegia

ABSTRACT The hereditary spastic paraplegias (HSPs), a group of neurodegenerative movement disorders, are among the genetically most heterogeneous clinical conditions. Still, the more than 50 forms known so far apparently explain less than 80% of cases. The present study identified two large HSP families, which seemed to show an autosomal recessive and an X‐linked inheritance pattern. A set of genetic analyses including exome sequencing revealed plausible mutations only when assuming incomplete/sex‐dependent penetrance of adjacent alterations in the autosomal dominant HSP gene ATL1 (c.1243C>T and c.1244G>A, respectively). By screening of additional HSP patients for the presence of these alterations, we identified three more cases and obtained additional evidence for reduced penetrance. Bisulfate sequencing and haplotype analysis indicated that c.1243C and c.1244G constitute a mutational hotspot. Our findings suggest that misinterpretation of inheritance patterns and, consequently, misselection of candidate genes to be screened in gene‐focused approaches contribute to the apparently missing heritability in HSP and, potentially, in other genetically heterogeneous disorders. Inheritance patterns usually guide gene selection in mutational screening strategies. By whole exome sequencing of index cases with apparently novel forms of spastic paraplegia, we identify a mutational hotspot in the known dominant gene ATL1 and show that corresponding alterations are associated with a highly reduced and partially sex‐dependent risk of developing the disease. Our findings suggest that misleading family history may contribute to missing heritability in genetically heterogeneous disorders