Human  -Mannosidase cDNA Characterization and First Identification of a Mutation Associated with Human  -Mannosidosis

Abstract

Human beta-mannosidosis is an autosomal recessive, lysosomal storage disease caused by a deficiency of the enzyme beta-mannosidase. Unlike the severe clinical manifestation of the disease in ruminants, in which it leads to neonatal death, the human disease phenotype is generally milder. In addition, the phenotypic manifestation among the reported cases of human beta-mannosidosis is variable, even among members of the same family. To understand the molecular basis of the human disease and the mechanisms for such clinical variability, we sequenced the entire coding region of the human beta-mannosidase gene using a combination of cDNA library screening, RT-PCR and 5' rapid amplification of cDNA ends (RACE). The composite cDNA is 3293 nt, consisting of an 87 nt 5'-untranslated region, 2640 nt coding region and 566 nt 3'-untranslated region. The gene was localized to human chromosome 4q22-25. Analysis of a multiple tissue northern blot demonstrated a single 3.7 kb transcript. Mutation analysis of a Czech gypsy family with two siblings differently affected with beta-mannosidosis demonstrated a homozygous A-->G transition 2 bp upstream of a splice acceptor site. The associated cryptic splice site activation and exon skipping caused by this mutation resulted in two abnormally spliced mutant mRNA species in both siblings.

Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent

“…Regionally specific myelin deficiency is present in the CNS but not in peripheral nerves Lovell and Jones 1983;Boyer et al 1990). In contrast with ruminant b-mannosidosis, human cases have a milder and heterogeneous clinical expression, even when caused by functionally null mutations (Alkhayat et al 1998;Bedilu et al 2002;Cooper et al 1990). The most severe cases are associated with intellectual disability, developmental delay, dysmorphology, frequent infections, and hearing loss.…”

“…One hypothesis is that protective factor(s) in the mixed strain mice, variable among animals, modifies the disease expression and determines differential susceptibility to phenotypic features such as neuronal vacuolation. Similar factors may be involved in the tremendous clinical heterogeneity among the small number of patients with b-mannosidosis, including intrafamilial variation and variation among patients with null mutations (Alkhayat et al 1998). Thus, for future studies of this animal model, it will be important to use the congenic 129X1/SvJ strain (or characterize the phenotype in a different uniform genetic background).…”

“…Introduction b-Mannosidosis (OMIM 248510) is a rare lysosomal storage disease that was first identified in Nubian goats (Jones and Dawson 1981;Jones and Laine 1981;Jones et al 1983) and later in Salers cattle Bryan et al 1993;Patterson et al 1991) and humans (Alkhayat et al 1998;Cooper et al 1986;Wenger et al 1986). This autosomal recessive inherited disorder of glycoprotein catabolism is caused by a deficiency of the lysosomal enzyme b-mannosidase (MANBA; EC 3.2.1.25, 609489).…”

Characterization of a β-D-mannosidase from a marine gastropod, Aplysia kurodai

“…To date, characterization and primary structure analysis of -mannosidase have been achieved in a few enzymes from bacteria (Duffaud et al, 1997;Stoll et al, 2000;Beki et al, 2003), fungi (Takada et al, 1999;Ademark et al, 2001), and mammals (Chen et al, 1995;Leipprandt et al, 1996;Alkhayat et al, 1998;Beccari et al, 2001). On the basis of the hydrophobic cluster analysis for their primary structures, most of these β-mannosidases were classified under glycosyl hydrolase-family 2 (GHF2) (Chen et al, 1995;Alkhayat et al, 1998;Takada et al, 1999;Ademark et al, 2001).…”

MANBApolymorphism was related to increased risk of colorectal cancer in Swedish but not in Chinese populations

“…The gene, MANBA, encoding for bmannosidase, comprises 17 exons and is located on chromosome 4q22-q25. It has been known that genetic deficiency of this enzyme results in betamannosidosis, a lysosomal storage disease that has a wide spectrum of neurological involvement [1].…”