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De novo mutation in KITLG gene causes a variant of Familial Progressive Hyper- and Hypo-pigmentation (FPHH).
Mol Genet Genomic Med. 2021 12; 9(12):e1841.MG

Abstract

Familial Progressive Hyper- and Hypopigmentation is a pigmentary disorder characterized by a mix of hypo- and hyperpigmented lesions, café-au-lait spots and hypopigmented ash-leaf macules. The disorder was previously linked to KITLG and various mutations have been reported to segregate in different families. Furthermore, association between KITLG mutations and malignancies was also suggested. Exome and SANGER sequencing were performed for identification of KITLG mutations. Functional in silico analyses were additionally performed to assess the findings. We identified a de novo mutation in exon 4 of KITLG gene causing NM_000899.4:c.[329A>T] (chr12:88912508A>T) leading to NP_000890.1:p.(Asp110Val) substitution in the 3rd alpha helix. It was predicted as pathogenic, located in a conserved region and causing an increase in hydrophobicity in the KITLG protein. Our findings clearly confirm an additional hot spot of KITLG mutations in the 3rd alpha helix, which very likely increases the risk of malignancies. To our knowledge the present study provides the strongest evidence of association of the KITLG mutation with both Familial Progressive Hyper- and Hypopigmentation and malignancy due to its' location on somatic cancer mutation locus. Additionally we also address difficulties with classification of the unique phenotype and propose a subtype within broader diagnosis.

Authors+Show Affiliations

Faculty of Medicine, Centre for Human Molecular Genetics and Pharmacogenomics, University of Maribor, Maribor, Slovenia.Faculty of Health Sciences, Department of Nursing, Maribor, Slovenia.Department of Dermatology and Venereal Diseases, University Clinical Centre Maribor, Maribor, Slovenia.Faculty of Medicine, Institute of Pathology, University of Ljubljana, Ljubljana, Slovenia.Faculty of Medicine, Centre for Human Molecular Genetics and Pharmacogenomics, University of Maribor, Maribor, Slovenia. Faculty of Chemistry and Chemical Engineering, Laboratory of Biochemistry, Molecular Biology and Genomics, University of Maribor, Maribor, Slovenia.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34716665

Citation

Gorenjak, Mario, et al. "De Novo Mutation in KITLG Gene Causes a Variant of Familial Progressive Hyper- and Hypo-pigmentation (FPHH)." Molecular Genetics & Genomic Medicine, vol. 9, no. 12, 2021, pp. e1841.
Gorenjak M, Fijačko N, Bogomir Marko P, et al. De novo mutation in KITLG gene causes a variant of Familial Progressive Hyper- and Hypo-pigmentation (FPHH). Mol Genet Genomic Med. 2021;9(12):e1841.
Gorenjak, M., Fijačko, N., Bogomir Marko, P., Živanović, M., & Potočnik, U. (2021). De novo mutation in KITLG gene causes a variant of Familial Progressive Hyper- and Hypo-pigmentation (FPHH). Molecular Genetics & Genomic Medicine, 9(12), e1841. https://doi.org/10.1002/mgg3.1841
Gorenjak M, et al. De Novo Mutation in KITLG Gene Causes a Variant of Familial Progressive Hyper- and Hypo-pigmentation (FPHH). Mol Genet Genomic Med. 2021;9(12):e1841. PubMed PMID: 34716665.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - De novo mutation in KITLG gene causes a variant of Familial Progressive Hyper- and Hypo-pigmentation (FPHH). AU - Gorenjak,Mario, AU - Fijačko,Nino, AU - Bogomir Marko,Pij, AU - Živanović,Milanka, AU - Potočnik,Uroš, Y1 - 2021/10/30/ PY - 2021/09/09/revised PY - 2021/01/20/received PY - 2021/10/17/accepted PY - 2021/10/31/pubmed PY - 2022/3/24/medline PY - 2021/10/30/entrez KW - KITLG KW - exome sequencing KW - familial progressive hyper- and hypo-pigmentation KW - gain-of-function SP - e1841 EP - e1841 JF - Molecular genetics & genomic medicine JO - Mol Genet Genomic Med VL - 9 IS - 12 N2 - Familial Progressive Hyper- and Hypopigmentation is a pigmentary disorder characterized by a mix of hypo- and hyperpigmented lesions, café-au-lait spots and hypopigmented ash-leaf macules. The disorder was previously linked to KITLG and various mutations have been reported to segregate in different families. Furthermore, association between KITLG mutations and malignancies was also suggested. Exome and SANGER sequencing were performed for identification of KITLG mutations. Functional in silico analyses were additionally performed to assess the findings. We identified a de novo mutation in exon 4 of KITLG gene causing NM_000899.4:c.[329A>T] (chr12:88912508A>T) leading to NP_000890.1:p.(Asp110Val) substitution in the 3rd alpha helix. It was predicted as pathogenic, located in a conserved region and causing an increase in hydrophobicity in the KITLG protein. Our findings clearly confirm an additional hot spot of KITLG mutations in the 3rd alpha helix, which very likely increases the risk of malignancies. To our knowledge the present study provides the strongest evidence of association of the KITLG mutation with both Familial Progressive Hyper- and Hypopigmentation and malignancy due to its' location on somatic cancer mutation locus. Additionally we also address difficulties with classification of the unique phenotype and propose a subtype within broader diagnosis. SN - 2324-9269 UR - https://wwww.unboundmedicine.com/medline/citation/34716665/De_novo_mutation_in_KITLG_gene_causes_a_variant_of_Familial_Progressive_Hyper__and_Hypo_pigmentation__FPHH__ L2 - https://doi.org/10.1002/mgg3.1841 DB - PRIME DP - Unbound Medicine ER -