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Case Report

Identification and Characterization of a Novel CLCN7 Variant Associated with Osteopetrosis

1
Bioinformatics Research Center, Pavlov First Saint Petersburg Medical State University, St. Petersburg 197022, Russia
2
R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg 197022, Russia
3
Pavlov First Saint Petersburg State Medical University Clinic, St. Petersburg 197022, Russia
4
Department of Microbiology and Translational Data Analytics Institute, The Ohio State University, Columbus, OH 43210, USA
*
Authors to whom correspondence should be addressed.
Genes 2020, 11(11), 1242; https://doi.org/10.3390/genes11111242
Received: 21 September 2020 / Revised: 12 October 2020 / Accepted: 19 October 2020 / Published: 22 October 2020
(This article belongs to the Section Human Genomics and Genetic Diseases)
Osteopetrosis is a group of rare inheritable disorders of the skeleton characterized by increased bone density. The disease is remarkably heterogeneous in clinical presentation and often misdiagnosed. Therefore, genetic testing and molecular pathogenicity analysis are essential for precise diagnosis and new targets for preventive pharmacotherapy. Mutations in the CLCN7 gene give rise to the complete spectrum of osteopetrosis phenotypes and are responsible for about 75% of cases of autosomal dominant osteopetrosis. In this study, we report the identification of a novel variant in the CLCN7 gene in a patient diagnosed with osteopetrosis and provide evidence for its significance (likely deleterious) based on extensive comparative genomics, protein sequence and structure analysis. A set of automated bioinformatics tools used to predict consequences of this variant identified it as deleterious or pathogenic. Structure analysis revealed that the variant is located at the same “hot spot” as the most common CLCN7 mutations causing osteopetrosis. Deep phylogenetic reconstruction showed that not only Leu614Arg, but any non-aliphatic substitutions in this position are evolutionarily intolerant, further supporting the deleterious nature of the variant. The present study provides further evidence that reconstructing a precise evolutionary history of a gene helps in predicting phenotypical consequences of variants of uncertain significance. View Full-Text
Keywords: genetics; comparative genomics; phylogenetic analysis; osteopetrosis; CLCN7 gene genetics; comparative genomics; phylogenetic analysis; osteopetrosis; CLCN7 gene
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MDPI and ACS Style

Bug, D.S.; Barkhatov, I.M.; Gudozhnikova, Y.V.; Tishkov, A.V.; Zhulin, I.B.; Petukhova, N.V. Identification and Characterization of a Novel CLCN7 Variant Associated with Osteopetrosis. Genes 2020, 11, 1242. https://doi.org/10.3390/genes11111242

AMA Style

Bug DS, Barkhatov IM, Gudozhnikova YV, Tishkov AV, Zhulin IB, Petukhova NV. Identification and Characterization of a Novel CLCN7 Variant Associated with Osteopetrosis. Genes. 2020; 11(11):1242. https://doi.org/10.3390/genes11111242

Chicago/Turabian Style

Bug, Dmitrii S., Ildar M. Barkhatov, Yana V. Gudozhnikova, Artem V. Tishkov, Igor B. Zhulin, and Natalia V. Petukhova 2020. "Identification and Characterization of a Novel CLCN7 Variant Associated with Osteopetrosis" Genes 11, no. 11: 1242. https://doi.org/10.3390/genes11111242

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