The first glycine‐to‐tryptophan substitution in the <i>COL1A1</i> gene identified in a patient with progressively‐deforming Osteogenesis imperfecta

Sałacińska, Kinga; Michałus, Izabela; Pinkier, Iwona; Rutkowska, Lena; Chlebna-Sokół, Danuta; Jakubowska-Pietkiewicz, Elżbieta; Kępczyński, Łukasz; Salachna, Dominik; Gach, Agnieszka

doi:10.1002/mgg3.1996

Cited by 3 publications

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“…Among seven distinct amino acids altering conservative glycine residues, we reported the first tryptophan substitution located in the COL1A1 gene. The novel variant c.733G>T p.(Gly245Trp), found in a patient with OI type 3, has been described in a separate publication by our team ( 10 ). A single in-frame deletion and insertion were observed in patients with progressively deforming and moderate outcomes, respectively; both were located in the α2 chain.…”

Section: Resultsmentioning

confidence: 90%

NGS analysis of collagen type I genes in Polish patients with Osteogenesis imperfecta: a nationwide multicenter study

Sałacińska,

Pinkier,

Rutkowska

et al. 2023

Front. Endocrinol.

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Osteogenesis imperfecta (OI) is a rare genetic disorder of the connective tissue. It presents with a wide spectrum of skeletal and extraskeletal features, and ranges in severity from mild to perinatal lethal. The disease is characterized by a heterogeneous genetic background, where approximately 85%–90% of cases have dominantly inherited heterozygous pathogenic variants located in the COL1A1 and COL1A2 genes. This paper presents the results of the first nationwide study, performed on a large cohort of 197 Polish OI patients. Variants were identified using a next-generation sequencing (NGS) custom gene panel and multiplex ligation probe amplification (MLPA) assay. The following OI types were observed: 1 (42%), 2 (3%), 3 (35%), and 4 (20%). Collagen type I pathogenic variants were reported in 108 families. Alterations were observed in α1 and α2 in 70% and 30% of cases, respectively. The presented paper reports 97 distinct causative variants and expands the OI database with 38 novel pathogenic changes. It also enabled the identification of the first glycine-to-tryptophan substitution in the COL1A1 gene and brought new insights into the clinical severity associated with variants localized in “lethal regions”. Our results contribute to a better understanding of the clinical and genetic aspects of OI.

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Section: Resultsmentioning

confidence: 90%

NGS analysis of collagen type I genes in Polish patients with Osteogenesis imperfecta: a nationwide multicenter study

Sałacińska,

Pinkier,

Rutkowska

et al. 2023

Front. Endocrinol.

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The first glycine‐to‐tryptophan substitution in the COL1A1 gene identified in a patient with progressively‐deforming Osteogenesis imperfecta

Sałacińska

Michałus

Pinkier

et al. 2022

Molec Gen & Gen Med

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Background Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue with variable phenotype and heterogeneous genetic background. Majority of reported mutations are glycine substitutions, whose clinical outcome ranges from mild to perinatal lethal. The phenotype appears to be influenced by the properties of amino acid side chain and the degree of structural aberration of collagen molecules. Since the genotype–phenotype correlation remains unclear, the severity of mutation is mostly predicted according to previously‐reported cases. Although the number of OI variants is constantly expanding, no glycine‐to‐tryptophan substitutions have been reported in COL1A1 gene. Methods A sample from a 15‐year‐old girl presenting with progressively‐deforming OI type III was tested using an NGS custom gene panel. Multiple bioinformatic and interpretation tools, including mutation databases and conservation analysis, were used for variant classification. The presence of the mutation was verified by Sanger sequencing. Results A novel heterozygous mutation c.733G>T was identified in the COL1A1 gene (p.Gly245Trp). Conclusions The discovery of this novel glycine‐to‐tryptophan substitution located in the COL1A1 gene broadens the spectrum of mutations underlying this rare disease and provides useful information on the clinical outcome of such substitutions.

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Impact of Missense Mutations on Spike Protein Stability and Binding Affinity in the Omicron Variant

Mahase,

Sobitan,

Yao

et al. 2024

Viruses

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The global effort to combat the COVID-19 pandemic faces ongoing uncertainty with the emergence of Variants of Concern featuring numerous mutations on the Spike (S) protein. In particular, the Omicron Variant is distinguished by 32 mutations, including 10 within its receptor-binding domain (RBD). These mutations significantly impact viral infectivity and the efficacy of vaccines and antibodies currently in use for therapeutic purposes. In our study, we employed structure-based computational saturation mutagenesis approaches to predict the effects of Omicron missense mutations on RBD stability and binding affinity, comparing them to the original Wuhan-Hu-1 strain. Our results predict that mutations such as G431W and P507W induce the most substantial destabilizations in the Wuhan-Hu-1-S/Omicron-S RBD. Notably, we postulate that mutations in the Omicron-S exhibit a higher percentage of enhancing binding affinity compared to Wuhan-S. We found that the mutations at residue positions G447, Y449, F456, F486, and S496 led to significant changes in binding affinity. In summary, our findings may shed light on the widespread prevalence of Omicron mutations in human populations. The Omicron mutations that potentially enhance their affinity for human receptors may facilitate increased viral binding and internalization in infected cells, thereby enhancing infectivity. This informs the development of new neutralizing antibodies capable of targeting Omicron’s immune-evading mutations, potentially aiding in the ongoing battle against the COVID-19 pandemic.

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The first glycine‐to‐tryptophan substitution in the COL1A1 gene identified in a patient with progressively‐deforming Osteogenesis imperfecta

Cited by 3 publications

References 14 publications

NGS analysis of collagen type I genes in Polish patients with Osteogenesis imperfecta: a nationwide multicenter study

NGS analysis of collagen type I genes in Polish patients with Osteogenesis imperfecta: a nationwide multicenter study

The first glycine‐to‐tryptophan substitution in the COL1A1 gene identified in a patient with progressively‐deforming Osteogenesis imperfecta

Impact of Missense Mutations on Spike Protein Stability and Binding Affinity in the Omicron Variant

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