Bedilu Rebecca, Nummy Katherine A, Cooper Alan, Wevers Ron, Smeitink Jan, Kleijer Wim J, Friderici Karen H
Department of Microbiology and Molecular Genetics, 5163 Biomedical and Physical Sciences Building, Michigan State University, East Lansing, MI 48824, USA.
Mol Genet Metab. 2002 Dec;77(4):282-90. doi: 10.1016/s1096-7192(02)00172-5.
Beta-mannosidosis is an autosomal recessive lysosomal storage disease resulting from a deficiency of the lysosomal enzyme beta-mannosidase. The clinical manifestations of this disease in reported human cases are very heterogeneous ranging from relatively mild to moderately severe. This is in contrast with the severe prenatal onset seen in ruminant beta-mannosidosis. In humans, mental retardation, hearing loss, frequent infections, and behavioral problems are relatively common. Dysmorphology and skeletal involvement such as those seen in ruminants are unusual. The purpose of this study is to determine the range of clinical expression in human beta-mannosidosis resulting from null mutations. We determined that the beta-mannosidase gene consists of 17 exons. Intron-based PCR primers were designed and used to amplify each of the exons in genomic DNA isolated from patient fibroblasts. We identified two patients with null mutations. Results of the analysis showed that one patient was heterozygous for nonsense mutations G334T (E83X) in exon 2 and C1363T (Q426X) in exon 10, resulting in truncation of the deduced peptide sequence from 879 to 82 and 425 amino acids, respectively. The second patient was homozygous for a deletion mutation in exon 11 (1541delAT). This deletion causes a reading frame shift and 26 out of frame amino acids before a stop codon occurs in exon 12, resulting in truncation of the deduced peptide sequence from 879 to 510 amino acids. Because disease presentation in these patients with null mutations is very variable, ranging from mild to severe, we conclude that beta-mannosidosis in humans may indeed be milder than typical of other lysosomal storage disorders.
β-甘露糖苷贮积症是一种常染色体隐性溶酶体贮积病，由溶酶体酶β-甘露糖苷酶缺乏所致。在已报道的人类病例中，该疾病的临床表现差异很大，从相对轻微到中度严重不等。这与反刍动物β-甘露糖苷贮积症严重的产前发病情况形成对比。在人类中，智力迟钝、听力丧失、频繁感染和行为问题相对常见。反刍动物中出现的畸形和骨骼受累情况在人类中并不常见。本研究的目的是确定由无效突变导致的人类β-甘露糖苷贮积症的临床表型范围。我们确定β-甘露糖苷酶基因由17个外显子组成。设计了基于内含子的PCR引物，并用于扩增从患者成纤维细胞分离的基因组DNA中的每个外显子。我们鉴定出两名具有无效突变的患者。分析结果显示，一名患者在外显子2中存在无义突变G334T（E83X），在外显子10中存在C1363T（Q426X），均为杂合子，导致推导的肽序列分别从879个氨基酸截短至82个和425个氨基酸。第二名患者在外显子11（1541delAT）中存在缺失突变，为纯合子。该缺失导致读码框移位，并在第12外显子出现终止密码子之前产生26个框外氨基酸，导致推导的肽序列从879个氨基酸截短至510个氨基酸。由于这些具有无效突变的患者的疾病表现差异很大，从轻度到重度不等，我们得出结论，人类β-甘露糖苷贮积症可能确实比其他典型的溶酶体贮积症症状较轻。
