A possible founder mutation in FZD6 gene in a Turkish family with autosomal recessive nail dysplasia.
Adult
Amino Acid Sequence
Codon, Nonsense
Consanguinity
Female
Frameshift Mutation
Frizzled Receptors
/ chemistry
Genetic Association Studies
Genetic Predisposition to Disease
Homozygote
Humans
Models, Molecular
Mutation
Nails, Malformed
/ genetics
Pedigree
Protein Conformation
Sequence Analysis
Sequence Deletion
Turkey
Autosomal recessive
Consanguinity
FZD6
Nail dysplasia
Turkey
Whole exome sequencing
Journal
BMC medical genetics
ISSN: 1471-2350
Titre abrégé: BMC Med Genet
Pays: England
ID NLM: 100968552
Informations de publication
Date de publication:
14 01 2019
14 01 2019
Historique:
received:
27
07
2018
accepted:
04
01
2019
entrez:
16
1
2019
pubmed:
16
1
2019
medline:
20
8
2019
Statut:
epublish
Résumé
Autosomal recessive nail dysplasia is characterized by thick and hard nails with a very slow growth on the hands and feet. Mutations in FZD6 gene were found to be associated with autosomal recessive nail dysplasia in 2011. Presently, only seven mutations have been reported in FZD6 gene; five mutations are clustered in the C-terminus, one is at the seventh transmembrane domain, and another is at the very beginning of third extracellular loop. Whole exome sequencing (WES) was applied to the index case, her one affected sister and her healthy consanguineous parents. The mutation was verified via Sanger sequencing. Molecular dynamics simulations of the predicted structures of native and mutant proteins were compared to gain insight into the pathogenicity mechanism of the mutation. Here, we report a homozygous 8 bp deletion mutation, p.Gly559Aspfs*16; c.1676_1683delGAACCAGC, in FZD6 gene which causes a frameshift and creates a premature stop codon at position 16 of the new reading frame. Our molecular dynamics calculations predict that the pathogenicity of this frameshift mutation may be caused by the change in entropy of the protein with negative manner, disturbing the C-terminal domain structure, and hence interaction partners of FZD6. We identified a homozygous deletion mutation in FZD6 in a consanguineous Turkish family with nail dysplasia. We also provide a molecular mechanism about the effects of the deletion on the protein structure and its possible motions. This study provides a pathogenicity mechanism for this mutation in nail dysplasia for the first time.
Sections du résumé
BACKGROUND
Autosomal recessive nail dysplasia is characterized by thick and hard nails with a very slow growth on the hands and feet. Mutations in FZD6 gene were found to be associated with autosomal recessive nail dysplasia in 2011. Presently, only seven mutations have been reported in FZD6 gene; five mutations are clustered in the C-terminus, one is at the seventh transmembrane domain, and another is at the very beginning of third extracellular loop.
METHODS
Whole exome sequencing (WES) was applied to the index case, her one affected sister and her healthy consanguineous parents. The mutation was verified via Sanger sequencing. Molecular dynamics simulations of the predicted structures of native and mutant proteins were compared to gain insight into the pathogenicity mechanism of the mutation.
RESULTS
Here, we report a homozygous 8 bp deletion mutation, p.Gly559Aspfs*16; c.1676_1683delGAACCAGC, in FZD6 gene which causes a frameshift and creates a premature stop codon at position 16 of the new reading frame. Our molecular dynamics calculations predict that the pathogenicity of this frameshift mutation may be caused by the change in entropy of the protein with negative manner, disturbing the C-terminal domain structure, and hence interaction partners of FZD6.
CONCLUSION
We identified a homozygous deletion mutation in FZD6 in a consanguineous Turkish family with nail dysplasia. We also provide a molecular mechanism about the effects of the deletion on the protein structure and its possible motions. This study provides a pathogenicity mechanism for this mutation in nail dysplasia for the first time.
Identifiants
pubmed: 30642273
doi: 10.1186/s12881-019-0746-6
pii: 10.1186/s12881-019-0746-6
pmc: PMC6332616
doi:
Substances chimiques
Codon, Nonsense
0
FZD6 protein, human
0
Frizzled Receptors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
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