A recurring NFS1 pathogenic variant causes a mitochondrial disorder with variable intra-familial patient outcomes
| Autor: | Adi Mory, Jeffrey Staples, Alina Kurolap, Hanna Mandel, Elena Dumin, Ann Saada, Karlla W. Brigatti, Claudia Gonzaga-Jauregui, Galit Tal, Tova Hershkovitz, Hagit Baris Feldman, Tamar Paperna |
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| Rok vydání: | 2021 |
| Předmět: |
Mitochondrial disease
Respiratory chain NFS1 Biology 03 medical and health sciences 0302 clinical medicine Endocrinology Genetics medicine Missense mutation lcsh:QH301-705.5 Molecular Biology Gene Exome sequencing lcsh:R5-920 0303 health sciences Intra-familial variability 030305 genetics & heredity Haplotype medicine.disease Phenotype Hot-spot variant Mitochondrial respiratory chain lcsh:Biology (General) Iron‑sulfur clusters lcsh:Medicine (General) 030217 neurology & neurosurgery |
| Zdroj: | Molecular Genetics and Metabolism Reports, Vol 26, Iss, Pp 100699-(2021) |
| ISSN: | 2214-4269 |
| DOI: | 10.1016/j.ymgmr.2020.100699 |
| Popis: | Iron‑sulfur clusters (FeSCs) are vital components of a variety of essential proteins, most prominently within mitochondrial respiratory chain complexes I-III; Fe-S assembly and distribution is performed via multi-step pathways. Variants affecting several proteins in these pathways have been described in genetic disorders, including severe mitochondrial disease. Here we describe a Christian Arab kindred with two infants that died due to mitochondrial disorder involving Fe-S containing respiratory chain complexes and a third sibling who survived the initial crisis. A homozygous missense variant in NFS1: c.215G>A; p.Arg72Gln was detected by whole exome sequencing. The NFS1 gene encodes a cysteine desulfurase, which, in complex with ISD11 and ACP, initiates the first step of Fe-S formation. Arginine at position 72 plays a role in NFS1-ISD11 complex formation; therefore, its substitution with glutamine is expected to affect complex stability and function. Interestingly, this is the only pathogenic variant ever reported in the NFS1 gene, previously described once in an Old Order Mennonite family presenting a similar phenotype with intra-familial variability in patient outcomes. Analysis of datasets from both populations did not show a common haplotype, suggesting this variant is a recurrent de novo variant. Our report of the second case of NFS1-related mitochondrial disease corroborates the pathogenicity of this recurring variant and implicates it as a hot-spot variant. While the genetic resolution allows for prenatal diagnosis for the family, it also raises critical clinical questions regarding follow-up and possible treatment options of severely affected and healthy homozygous individuals with mitochondrial co-factor therapy or cysteine supplementation. |
| Databáze: | OpenAIRE |
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