Spectrum of mutations in fucosidosis

Abstract

Fucosidosis is a lysosomal storage disorder characterised by progressive psychomotor deterioration, angiokeratoma and growth retardation. It is due to deficient α-l-fucosidase activity leading to accumulation of fucose-containing glycolipids and glycoproteins in various tissues. Fucosidosis is extremely rare with less than 100 patients reported worldwide, although the disease occurs at a higher rate in Italy, in the Hispanic-American population of New Mexico and Colorado, and in Cuba. We present here a review study of the mutational spectrum of fucosidosis. Exon by exon mutation analysis of FUCA1, the structural gene of α-l-fucosidase, has identified the mutation(s) in nearly all fucosidosis patients investigated. The spectrum of the 22 mutations detected to date includes four missense mutations, 17 nonsense mutations consisting of seven stop codon mutations, six small deletions, two large deletions, one duplication, one small insertion and one splice site mutation. All these mutations lead to nearly absent enzymatic activity and severely reduced cross-reacting immunomaterial. The observed clinical variability is, therefore, not due to the nature of the fucosidosis mutation, but to secondary unknown factors.

Mutation identification and characterization of a Taiwanese patient with fucosidosis

“…This is in agreement with nearly absent a-L-fucosidase activity for other FUCA1 mutations reported (Fleming et al 1998;Akagi et al 1999;Willems et al 1999;Ip et al 2002). Neither splicing (http://www.es.embnet.org/~mwang/assp.html) nor the mRNA level (Fig.…”

“…The spectrum of the mutations reported includes 5 missense mutations and 21 null mutations consisting of 9 stop codon mutations, 6 small deletions, 3 large deletions, 1 duplication, 1 small insertion, and 1 splice site mutation. Most mutations led to nearly absent enzymatic activity and severely reduced cross-reacting immunomaterial (Fleming et al 1998;Akagi et al 1999;Willems et al 1999;Ip et al 2002). Therefore, the observed clinical variability was considered to be due to secondary unknown factors.…”

Novel mutations in the FUCA1 gene that cause fucosidosis

“…The mutations are distributed along the coding region of FUCA1. They are located in the glycoside hydrolase domain (catalytic domain, amino acid residues 35-370) and the C-terminal domain (amino acid residues 372-463) of a-L-fucosidase, and result in nearly absent enzymatic activity (Willems et al, 1999) (Human Gene Mutation Database, http://www.hgmd.cf.ac.uk, accessed on June, 2016.…”

Structure and Substrate Specificity of a Eukaryotic Fucosidase from Fusarium graminearum

“…Human GH29 fucosidases, FUCA1 and FUCA2, are both active on ␣1,2/3/4/6-linked fucosyl substrates as well as pNP-Fuc (20,21,31,34). FUCA1 is a lysosomal enzyme whose deficiency causes fucosidosis, a disease characterized by progressive mental and motor deterioration (2). FUCA2 is a secreted enzyme and is essential for Helicobacter pylori adhesion during infection of gastric cancer cells (34).…”

“…Fucose (Fuc), 2 although relatively low in abundance in the biosphere, has many important functions. In mammals L-Fuccontaining conjugates in the form of glycans, glycoproteins, or glycolipids in particular are involved in forming structural determinants of ABO blood group antigens, mediating hostmicrobe interactions, leukocyte-endothelial adhesion, fertilization and embryonic development, and signal transduction via O-fucosylation directly on Ser and Thr of specific types of protein modules as well as implicated in various human disease states including cancer, inflammation, and fucosidosis (1)(2)(3)(4).…”