Fucosidosis is a rare lysosomal storage disorder caused by the

inherited deficiency of the lysosomal hydrolase α-L-fucosidase, which

leads to an impaired degradation of fucosylated glycoconjugates.

Here, we report the generation of a fucosidosis mouse model, in

which the gene for lysosomal α-L-fucosidase (Fuca1) was disrupted

by gene targeting. Homozygous knockout mice completely lack

α-L-fucosidase activity in all tested organs leading to highly

elevated amounts of the core-fucosylated glycoasparagine Fuc

(α1,6)-GlcNAc(β1-N)-Asn and, to a lesser extent, other fucosylated

glycoasparagines, which all were also partially excreted in urine.

Lysosomal storage pathology was observed in many visceral organs,

such as in the liver, kidney, spleen and bladder, as well as in the

central nervous system (CNS). On the cellular level, storage was

characterized by membrane-limited cytoplasmic vacuoles primarily

containing water-soluble storage material. In the CNS, cellular

alterations included enlargement of the lysosomal compartment in

various cell types, accumulation of secondary storage material and

neuroinflammation, as well as a progressive loss of Purkinje cells

combined with astrogliosis leading to psychomotor and memory

deficits. Our results demonstrate that this new fucosidosis mouse

model resembles the human disease and thus will help to unravel

underlying pathological processes. Moreover, this model could be

utilized to establish diagnostic and therapeutic strategies for fucosidosis.