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Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia.


ABSTRACT: Hereditary spastic paraplegias (HSPs) form a heterogeneous group of neurological disorders. A whole-genome linkage mapping effort was made with three HSP-affected families from Spain, Portugal, and Tunisia and it allowed us to reduce the SPG26 locus interval from 34 to 9 Mb. Subsequently, a targeted capture was made to sequence the entire exome of affected individuals from these three families, as well as from two additional autosomal-recessive HSP-affected families of German and Brazilian origins. Five homozygous truncating (n = 3) and missense (n = 2) mutations were identified in B4GALNT1. After this finding, we analyzed the entire coding region of this gene in 65 additional cases, and three mutations were identified in two subjects. All mutated cases presented an early-onset spastic paraplegia, with frequent intellectual disability, cerebellar ataxia, and peripheral neuropathy as well as cortical atrophy and white matter hyperintensities on brain imaging. B4GALNT1 encodes ?-1,4-N-acetyl-galactosaminyl transferase 1 (B4GALNT1), involved in ganglioside biosynthesis. These findings confirm the increasing interest of lipid metabolism in HSPs. Interestingly, although the catabolism of gangliosides is implicated in a variety of neurological diseases, SPG26 is only the second human disease involving defects of their biosynthesis.

SUBMITTER: Boukhris A 

PROVIDER: S-EPMC3710753 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia.

Boukhris Amir A   Schule Rebecca R   Loureiro José L JL   Lourenço Charles Marques CM   Mundwiller Emeline E   Gonzalez Michael A MA   Charles Perrine P   Gauthier Julie J   Rekik Imen I   Acosta Lebrigio Rafael F RF   Gaussen Marion M   Speziani Fiorella F   Ferbert Andreas A   Feki Imed I   Caballero-Oteyza Andrés A   Dionne-Laporte Alexandre A   Amri Mohamed M   Noreau Anne A   Forlani Sylvie S   Cruz Vitor T VT   Mochel Fanny F   Coutinho Paula P   Dion Patrick P   Mhiri Chokri C   Schols Ludger L   Pouget Jean J   Darios Frédéric F   Rouleau Guy A GA   Marques Wilson W   Brice Alexis A   Durr Alexandra A   Zuchner Stephan S   Stevanin Giovanni G  

American journal of human genetics 20130606 1


Hereditary spastic paraplegias (HSPs) form a heterogeneous group of neurological disorders. A whole-genome linkage mapping effort was made with three HSP-affected families from Spain, Portugal, and Tunisia and it allowed us to reduce the SPG26 locus interval from 34 to 9 Mb. Subsequently, a targeted capture was made to sequence the entire exome of affected individuals from these three families, as well as from two additional autosomal-recessive HSP-affected families of German and Brazilian origi  ...[more]

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