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 β-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.

Figure 1

SPG26 Pedigrees and Segregation of the Mutations Detected in B4GALNT1 Square symbols indicate males and circles indicate females. Filled symbols indicate affected individuals. The numbers are an internal reference for each sampled individual. Stars indicate sampled subjects. Abbreviations are as follows: M, mutation; +, wild-type.

Figure 2

Schematic Representation of B4GALNT1/SPG26 and Location of the Mutations (A) Exon-intron structure of B4GALNT1, with positions of mutations identified in seven SPG26-affected families. Exons are indicated as black boxes. The region encoding a functional domain is indicated by blue bars. (B) Phylogenetic conservation of three amino acids mutated in SPG26-affected individuals. (C) Electropherograms of the mutations identified. Mutation nomenclature is in agreement with ALAMUT 2.2 and Mutalyzer software with transcript NM_001478.3.

Figure 3

Simplified Representation of Ganglioside Metabolism and Their Related Disorders Arrows indicate the orientation of the enzymatic reactions and the corresponding enzymes are indicated in black. Metabolic diseases are indicated in blue at the corresponding altered reaction. Ganglioside formation is performed in the endoplasmic reticulum and Golgi by successive glycosylations. Their degradation takes place in lysosomes. Abbreviations are as follows: hex, hexosaminidase; Gb3, globotrioaosylceramide; GBA, glucocerebrosidase; GD, disialic ganglioside; GALC, galactosylceramide-beta-galactosidase; GLA, alpha galactosidase; GLB, beta galactosidase; GM, monosialic ganglioside; GT, trisialic ganglioside; GT3 synthase, alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase; MLD, metachromatic leukodystrophy; Sap, saposin.