Rare missense variant p.Ala505Ser in the ZAK protein observed in a patient with split-hand/foot malformation from a non-consanguineous pedigree
العنوان: | Rare missense variant p.Ala505Ser in the ZAK protein observed in a patient with split-hand/foot malformation from a non-consanguineous pedigree |
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المؤلفون: | Charles E. Schwartz, Yunhui Peng, Anna V. Blenda, Robert G. Best, Christopher Ronald Funk, Ekaterina Michonova, Melanie M. May, Elizabeth S Huey |
المصدر: | The Journal of International Medical Research Journal of International Medical Research, Vol 48 (2020) |
سنة النشر: | 2020 |
مصطلحات موضوعية: | Models, Molecular, Leucine zipper, Medicine (General), chromosome region 7q21.3-q22.1 (chr. 7q21), Foot malformation, Protein Conformation, DNA Mutational Analysis, Limb Deformities, Congenital, Mutation, Missense, Single-nucleotide polymorphism, 030204 cardiovascular system & hematology, Split-hand/foot malformation (SHFM), Biochemistry, Polymorphism, Single Nucleotide, distal-less homeobox-5 (DLX5), Evolution, Molecular, Pre-Clinical Research Report, 03 medical and health sciences, Split-Hand/Foot Malformation, Mice, Structure-Activity Relationship, 0302 clinical medicine, R5-920, leucine zipper containing kinase AZK (ZAK), Medicine, Missense mutation, Animals, Humans, Genetic Predisposition to Disease, Gene, Alleles, Genetic Association Studies, Genetics, Mice, Knockout, business.industry, Biochemistry (medical), Cell Biology, General Medicine, MAP Kinase Kinase Kinases, distal-less homeobox-6 (DLX6), Disease Models, Animal, Amino Acid Substitution, 030220 oncology & carcinogenesis, apical ectodermal ridge (AER), Chromosome Deletion, business, Chromosomes, Human, Pair 7, Signal Transduction |
الوصف: | Objective Split-hand/foot malformation (SHFM) is a rare, often debilitating, congenital limb malformation. A single nucleotide polymorphism within the leucine zipper containing kinase AZK ( ZAK ) gene was recently associated with SHFM in two consanguineous Pakistani pedigrees. We hypothesized that additional unrelated patients with the phenotype may carry a pathogenic mutation in ZAK . Methods DNA samples were collected from 38 patients with SHFM and associated hearing loss for Sanger DNA sequencing and in silico analysis. Results Two missense mutations within ZAK were detected in 11 patients, but only one missense variant, p.Ala505Ser, occurred with a presumed rare allele frequency. In silico modeling of the ZAK protein with the p.Ala505Ser substitution indicated a negative binding free energy change (mean ΔΔG = −0.9), representing destabilization of the ZAK tertiary structure. Additional laboratory analysis demonstrated a chromosome region 7q21.3-q22.1 deletion. This locus contains the SHFM-1 causative genes SHFM1 , DLX5 , and DLX6 (distal-less homeobox-5 and -6). Conclusions We report a novel and rare missense variant, ZAK p.Ala505Ser, in one patient with SHFM from a non-consanguineous pedigree. This variant mildly destabilizes the ZAK tertiary structure. Although this mutation involved a deletion at the SHFM1 locus (7q21.3-q22.1), ZAK signaling destabilization may have contributed to the phenotype, which included hearing loss. |
تدمد: | 1473-2300 |
URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4ed99970053b8a10fca02a6746bdf47a https://pubmed.ncbi.nlm.nih.gov/32266845 |
Rights: | OPEN |
رقم الانضمام: | edsair.doi.dedup.....4ed99970053b8a10fca02a6746bdf47a |
قاعدة البيانات: | OpenAIRE |
تدمد: | 14732300 |
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