Novel Mutations in Sandhoff Disease: A Molecular Analysis among Iranian Cohort of Infantile Patients

Background Sandhoff disease is an autosomal recessive disorder caused by β-hexosaminidase deficiency and accumulation of GM2 ganglioside resulting in progressive motor neuron manifestations and death from respiratory failure and infections in infantiles. Pathogenic mutations in HEXB gene were observed which leads to enzyme activity reduction and interruption of normal metabolic cycle of GM2 ganglioside in sandhoff patients. Methods: Six infantile index patients with typical biochemical and clinical picture of the disease were studied at the molecular level. After DNA extraction and amplification, probands and their parents, were evaluated by direct sequencing of amplicons. Results: We identified 7 different mutations among which 4 were novel. The most prevalent finding (50%) among our population was a 16 kb deletion including the promoter and exons 1–5. The other findings included c.1552delG and c.410G>A, c.362 A>G, c.550delT, c.1597C>T, c.1752delTG. Conclusion: We conclude that Cys137Tyr and R533C mutations may be pathogenic because of changing amino acid and locating at the conserved region and also they have not been observed in hundred controls. Besides, four mutations including: Cys137Tyr, c.1552delG, c.1597C>T and c.550delT fulfilled almost criteria for pathogenic mutation.

[1]  Anuj Jain,et al.  Infantile Sandhoff's disease with peripheral neuropathy. , 2010, Pediatric neurology.

[2]  K. Vlahovicek,et al.  Molecular and functional analysis of the HEXB gene in Italian patients affected with Sandhoff disease: identification of six novel alleles , 2009, neurogenetics.

[3]  G. Pavesi,et al.  Phylogenetic analyses suggest multiple changes of substrate specificity within the Glycosyl hydrolase 20 family , 2008, BMC Evolutionary Biology.

[4]  C. Scriver,et al.  The Metabolic and Molecular Bases of Inherited Disease, 8th Edition 2001 , 2001, Journal of Inherited Metabolic Disease.

[5]  C. Argaraña,et al.  Sandhoff disease in Argentina: high frequency of a splice site mutation in the HEXB gene and correlation between enzyme and DNA-based tests for heterozygote detection , 1994, Human Genetics.

[6]  J. D. Vijlder,et al.  Demonstration of a Sandhoff disease-associated autosomal 50-kb deletion by field inversion gel electrophoresis , 1989, Human Genetics.

[7]  S. Shoji,et al.  Compound heterozygosity with two novel mutations in the HEXB gene produces adult Sandhoff disease presenting as a motor neuron disease phenotype , 2002, Journal of the Neurological Sciences.

[8]  K. Sandhoff,et al.  Complete analysis of the glycosylation and disulfide bond pattern of human beta-hexosaminidase B by MALDI-MS. , 2001, Glycobiology.

[9]  R. Dodelson de Kremer,et al.  A frequent TG deletion near the polyadenylation signal of the human HEXB gene: Occurrence of an irregular DNA structure and conserved nucleotide sequence motif in the 3′ untranslated region , 1998, Human mutation.

[10]  R. Proia,et al.  Molecular basis of heat labile hexosaminidase B among Jews and Arabs , 1997, Human mutation.

[11]  Toshiaki Tanaka,et al.  A Novel Missense Mutation (C522Y) Is Present in the β-Hexosaminidase β-Subunit Gene of a Japanese Patient with Infantile Sandhoff Disease , 1995 .

[12]  R. Proia,et al.  Structure and Expression of the Mouse β-Hexosaminidase Genes, Hexa and Hexb , 1994 .

[13]  E. Neuwelt,et al.  Characterization of the molecular defect in a feline model for type II GM2-gangliosidosis (Sandhoff disease). , 1994, The American journal of pathology.

[14]  R. Proia,et al.  Structure and expression of the mouse beta-hexosaminidase genes, Hexa and Hexb. , 1994, Genomics.

[15]  S. Tsuji,et al.  A novel exon mutation in the human beta-hexosaminidase beta subunit gene affects 3' splice site selection. , 1992, The Journal of biological chemistry.

[16]  D. Mahuran,et al.  Structure and distribution of an Alu-type deletion mutation in Sandhoff disease. , 1990, The Journal of clinical investigation.

[17]  S. Schuster,et al.  Characterization of the human HEXB gene encoding lysosomal β-hexosaminidase , 1988 .

[18]  S. Schuster,et al.  Characterization of the human HEXB gene encoding lysosomal beta-hexosaminidase. , 1988, Genomics.