Exome sequencing of a Pakistani family with spastic paraplegia identified an 18 bp deletion in the cytochrome B5 domain of FA2H
| Autor: | Khurram Rehman, Beatrice A. Brugger, Julian Wenninger, Safdar Abbas, Muzammil Ahmad Khan, Sana Gul, Christian Windpassinger, Jasmin Blatterer, Benjamin Tatrai, Muhammad Zubair |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Adult Male Cytochrome Adolescent Hereditary spastic paraplegia Biology medicine.disease_cause Polymorphism Single Nucleotide Mixed Function Oxygenases 03 medical and health sciences Exon GJC2 Consanguinity 0302 clinical medicine Cytochrome b5 Exome Sequencing medicine Humans Family Pakistan Gene Exome sequencing Genetics Mutation Spastic Paraplegia Hereditary General Medicine medicine.disease Pedigree Molecular Docking Simulation 030104 developmental biology Cytochromes b5 Neurology biology.protein Female Neurology (clinical) 030217 neurology & neurosurgery |
| Zdroj: | Neurological research. 43(2) |
| ISSN: | 1743-1328 |
| Popis: | Hereditary spastic paraplegias (HSPs) are a diverse class of neurodegenerative disorders that mainly affect the corticospinal tract of the body and result in various clinical conditions such as lower limb spasticity and muscle weakness in the lower extremities. Worldwide, more than 70 chromosomal loci/genes have been reported to be associated with HSPs, out of which, six genes viz., ATL1, FA2H, GJC2, AP4E1, ALDH18A1 and ATP13A2 have been mapped in Pakistani families. In the present genetic study, we report on a large consanguineous Pakistani family with a complex form of HSP segregating with a 18 bp deletion in the first exon of the Fatty Acid 2-Hydroxylase (FA2H) gene (NM_024306.5:c.159_176del). The identified in-frame deletion results in loss of six amino acids (p.Arg53_Ile58del) within the cytochrome B5 domain of the protein. FA2H is required for alpha-hydroxylation of free fatty acids to form alpha-hydroxylated sphingolipids. Its cytochrome b5-like heme-binding domain, which spans from residues 15 to 85, imparts the redox activity to FA2H. This mutation has previously been reported in a Pakistani family presenting with a similar form of complex HSP. Together with our findings the pathogenic role of the observed variant is further supported. Mutation studies on additional Pakistani families for FA2H will further elucidate its mutational spectrum, which may help in developing a prenatal diagnostic test for Khyber Pakhtunkhwa resident Pakistani families. |
| Databáze: | OpenAIRE |
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