Abstract
Sandhoff disease is a rare neurodegenerative and autosomal recessive disorder, which is characterized by a defect in ganglioside metabolism. Also, it is caused by mutations in the HEXB gene for the β-subunit isoform 1 of β-N-acetyl hexosaminidase. In the present study, an Iranian 14- month -old girl with 8- month history of unsteady walking and involuntary movements was described. In this regard, biochemical testing showed some defects in the normal activity of beta-hexosaminidase protein. Following sequencing of HEXB gene, a homozygous c.833C > T mutation was identified in the patient’s genome. After recognition of p.A278V, several different in silico methods were used to assess the mutant protein stability, ranging from mutation prediction methods to ligand docking. The p.A278V mutation might be disruptive because of changing the three-dimensional folding at the end of the 5th alpha helix. According to the medical prognosis, in silico and structural analyses, it was predicted to be disease cause.
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Data Availability
The activity of β-Hexosaminidase was measured via dried blood spots (DBSs) on filter.
Genomic DNA extraction using FlexiGene DNA Kit (QIAGEN).
Sequencing on an ABI 3700 sequencer (Kosar Company, Tehran).
The sequence alteration was assessed by the in-silico prediction algorithms SIFT and Polyphen-2.
The structures of Beta-hexosaminidase subunit beta using UCSF Chimera 1.8.1, online Swiss-Prot server, RaptorX.
protein–ligand docking was calculated from Hex 8.0.0 software.
Abbreviations
- GDL:
-
2-Acetamido-2-Deoxy-D-Glucono-1,5-Lactone
- NAG:
-
N-acetyl-d-lucosamine
- EDO:
-
1,2-ethanediol
- MRI:
-
Brain magnetic resonance imaging
- MD:
-
Molecular Dynamics
- DBSs:
-
Dried blood spots
- PDB:
-
Protein databank
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Acknowledgements
We thank the parent s patient and also thank all physicians who supported us via examination, provision of blood samples and etc.
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Z Rahmani was the major contributor in writing the manuscript, involved in protein modelling and revision response. A Banisadr performed protein modeling, structure alignment and ligand docking, took part in writing the manuscript and revision response. V Ghodsinezhad investigated the phylogenetic background and performed in silico analysis, took part in writing the manuscript. M Dibaj help to find similar works and gave hand to justify the final version of manuscript. O Aryani diagnosed and interpreted the patient data regarding the sandhoff disease. Also supervised the whole project. All authors read and approved the final manuscript.
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Dr. Omid Aryani has recently passed away. This article is dedicated to him.
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Rahmani, Z., Banisadr, A., Ghodsinezhad, V. et al. P. Ala278Val mutation might cause a pathogenic defect in HEXB folding leading to the Sandhoff disease. Metab Brain Dis 37, 2669–2675 (2022). https://doi.org/10.1007/s11011-021-00669-9
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DOI: https://doi.org/10.1007/s11011-021-00669-9