TY - JOUR
T1 - Human β-mannosidase cDNA characterization and first identification of a mutation associated with human β-mannosidosis
AU - Alkhayat, Aisha H.
AU - Kraemer, Stacey A.
AU - Leipprandt, Jeffrey R.
AU - Macek, Milan
AU - Kleijer, Wim J.
AU - Friderici, Karen H.
N1 - Funding Information:
The authors thank Dr Margaret Jones for advice, critical reading of the manuscript and support of studies leading to this publication (NS16886). This work was also supported by a Michigan State University All University Research Initiation Grant (KHF), by NIH grant DK49782 (KHF), by an education grant (AHA) from Sultan Qaboos University, Sultanate of Oman and by grant IGA MZ CR no. 1148-6 (MM).
PY - 1998/1
Y1 - 1998/1
N2 - Human β-mannosidosis is an autosomal recessive, lysosomal storage disease caused by a deficiency of the enzyme β-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 β-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 β-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 β-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.
AB - Human β-mannosidosis is an autosomal recessive, lysosomal storage disease caused by a deficiency of the enzyme β-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 β-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 β-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 β-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.
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U2 - 10.1093/hmg/7.1.75
DO - 10.1093/hmg/7.1.75
M3 - Article
C2 - 9384606
AN - SCOPUS:0031975110
SN - 0964-6906
VL - 7
SP - 75
EP - 83
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 1
ER -