Novel mutations in a-mannosidosis. H.M.F. Riise1, T. Berg2, H. Klenow3, G. Evjen4, E. Breines3, O.K. Tollersrud4, O. Nilssen3. 1) Department of Human Genetics, UCLA, Los Angeles, CA, USA; 2) Department of Chemical Pathology, Womens and Childrens Hospital, Adelaide, Australia; 3) Department of Medical Genetics, University Hospital of Tromsø, Tromsø, Norway; 4) Department of Medical Biochemistry, University of Tromsø, Tromsø, Norway.
Lysosomal a-mannosidase (EC 3.2.1.24) is an exoglycosidase involved in the ordered degradation of N-linked oligosaccharides. Lack of LAMAN activity leads to the lysosomal storage disorder a-mannosidosis (MIM 248500), an autosomal recessive disorder described in man, cattle and cat. Affected individuals accumulate partially degraded oligosaccharides in the lysosomes, and typical symptoms in man are mental retardation, hearing loss, recurrent infections and various skeletal changes. Recently, we reported 23 disease causing mutations and six single nucleotide polymorphisms in the LAMAN gene of 42 unrelated a-mannosidosis patients mainly of European origin. In this work, 24 additional patients were analyzed by screening for known mutations as well as by automated DNA sequencing of the 24 LAMAN exons and exon-intron borders. Sixteen novel mutations; five missense, three nonsense, three splice site and five small insertions/deletions, were identified. In total, the 39 mutations were detected on 103 of the 132 alleles (78%). Most of the mutations were private or occurred in two or three families, except for one missense mutation, R750W, that was detected on 31 alleles (23.5%) in patients from 11 different countries. Haplotype analysis using four intragenic SNPs revealed that the 750W allele existed on three different haplotype backgrounds. The majority of the alleles (17 out of 20 ) shared the same haplotype, indicating that the 750W mutation probably spread by founder effects. The two other associated haplotypes could have emerged from the ancestral haplotype by single recombination events or, alternatively, resulted from recurrent mutations.