“Infantile GM1-gangliosidosis: new mutations in the b-galactosidase gene identified in two patients with cardiomyopathy”.

Program Nr: 2736 from the 1999 ASHG Annual Meeting Infantile GM1-gangliosidosis: new mutations in the bgalactosidase gene identified in two patients with cardiomyopathy. A. Morrone1, T. Bardelli1, A. Caciotti1, M.A. Donati1, G. De Gregorio1, A. d'Azzo2, E. Zammarchi1. 1) Dept. Pediatrics, Univ Florence, Florence, Florence, Italy; 2) Dept. of Genetics, St. Jude Hospital, Memphis, USA. Infantile GM1-gangliosidosis is a rare lysosomal storage disorder with autosomal recessive inheritance. The disease is caused by primary deficiency of acid b-Galactosidase and it is clinically characterised by early psychomotor delay, severe and progressive neurological involvement. Death usually occurs within two years. The human b-galactosidase (Hb-Gal) gene gives rise to two alternatively spliced mRNAs: a major transcript (Hb-Gal long) of 2,5 kb that encodes the classical lysosomal form of the enzyme, and a minor transcript (Hb-Gal short) of 2.0 kb encoding Elastin Binding Protein (EBP). Here we report the identification of three new b-galactosidase gene mutations in total RNA and DNA preparations of an Italian and an American patients affected by infantile GM1 gangliosidosis with cardiomyopathy. In the Italian patient an out-of-frame Hb-Gal transcript with 154 bp insertion in E10/E11 was detected in combination with the previously reported stop codon mutation W92X. The aberrant Hb-Gal transcript, has also been confirmed in his father's mRNA. These genetic lesions give rise to aberrant mRNAs with a complete lack of function of both the lysosomal protein and EBP. In the American patient,two new transitions,C252T and C1356T,have been identified that results in the aminoacid substitutions R68W and L436F. In addition to these mutations,the previously reported R201C substitution was also identified in this patient. The R68W has been confirmed in the father's genomic DNA. Both L436F and R201C have been identified in the mother and sister. The mutation R201C, mapping in a CpG island of a region encoding only for the lysosomal enzyme, correlates with juvenile GM1-gangliosidosis phenotype. Therefore the severe clinical manifestations must be attributed with R68W/L436F. These aminoacid changes are present in the Hb-Gal premRNA region common between Hb-Gal long and Hb-Gal short, consequently both proteins are affected by the mutations.