Identification of novel missense HEXB gene mutation in Iranian-child with juvenile Sandhoff disease

- New pathogenic missense mutation in the HEXB gene was detected.
- Mutation c.821T > A in exon 7 of the HEXB gene is cause of Sandhoff disease.
- Protein modeling change p.Val274Glu in the HEXB gene reveals structural defects.

Sandhoff disease is an autosomal recessive lysosomal storage disease caused by mutation in the HEXB gene. Accumulation of GM2 gangliosides resulting in advanced motor neuron manifestation and death from respiratory failure and infections in infantiles. Pathogenic mutations in the HEXB gene were detected that leads to enzyme activity reduction and therefore interruption of normal metabolic cycles of GM2 ganglioside in Sandhoff patients. We included one Iranian 5-years-old female with typical biochemical and clinical symptoms of the juvenile Sandhoff disease. After DNA extraction and amplification, proband and her parents, were assessed by direct sequencing of the amplicons. In addition, homology modeling of the novel mutant protein has been conducted to reveal the structural defects caused by the mutation. New unreported pathogenic missense mutation c.821T > A (p.Val274Glu; Homozygous) in exon 7 of the HEXB gene was identified. The structural analysis also showed that the novel mutation is the cause of a serious structural deficiency and leads to abnormal enzyme activity. We concluded that missense mutation p.Val274Glu is pathogenic because of amino acid alteration and its location on the conserved region of the protein. Also, biochemical and structural analysis demonstrated defects in the normal function of beta-hexosaminidase protein.