Identification of a de novo mutation in KRT5 gene underlying epidermolysis bullosa simplex by whole exome sequencing in a Vietnamese patient

Authors

  • Ma Thi Huyen Thuong
  • Dang Tien Truong
  • Nguyen Hai Ha
  • Nguyen Dang Ton

DOI:

https://doi.org/10.15625/1811-4989/16111

Keywords:

Epidermolysis bullosa simplex, KRT5, Whole exome sequencing

Abstract

Epidermolysis bullosa simplex (EBS) is a group of epidermolysis bullosa (EB) and accounts for 75-85% EB cases. Most EBS patients are caused by mutations in KRT5 or KRT14, encoding for keratin 5 and keratin 14, respectively, which impair the structural entirety of paired intermediate filaments expressed in the fracture of basal keratinocytes and subsequent blistering of the epithelium. This study aimed to identify the causative mutation in a Vietnamese EB case. Whole exome sequencing (WES) was performed in the affected individual and revealed a de novo heterozygous pathogenic mutation in exon 7 of KRT5 gene, resulting in an amino acid change at position 477, with glutamic acid to lysine substitution (p.E477K). The KRT5 p.E477K was strong associated with the very severe or lethal of generalized severe EBS (GS-EBS), characterized by the severe symptoms at birth, improving with age and evolution to palmoplantar keratoderma and nail dysplasia. Our finding will aid the molecular diagnosis, prognosis prediction of the patient with GS-EBS due to p.E477K and significant genetic counselling the family concerning the recurrence risk for future pregnancies.

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References

Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4): 248-9.

Bardhan A, Bruckner-Tuderman L, Chapple ILC, Fine JD, Harper N, Has C, Magin TM, Marinkovich MP, Marshall JF, McGrath JA, Mellerio JE, Polson R, Heagerty AH (2020) Epidermolysis bullosa. Nat Rev Dis Primers 6(1): 78.

Coulombe PA ,Lee CH (2012) Defining keratin protein function in skin epithelia: epidermolysis bullosa simplex and its aftermath. J Invest Dermatol 132(3 Pt 2): 763-75.

Fine J-D, Bruckner-Tuderman L, Eady RAJ, Bauer EA, Bauer JW, Has C, Heagerty A, Hintner H, Hovnanian A, Jonkman MF, Leigh I, Marinkovich MP, Martinez AE, McGrath JA, Mellerio JE, Moss C, Murrell DF, Shimizu H, Uitto J, Woodley D, Zambruno G (2014) Inherited epidermolysis bullosa: Updated recommendations on diagnosis and classification. J Am Acad Dermatol 70(6): 1103-1126.

Hamada T, Kawano Y, Szczecinska W, Wozniak K, Yasumoto S, Kowalewski C, Hashimoto T (2005) Novel keratin 5 and 14 gene mutations in patients with epidermolysis bullosa simplex from Poland. Arch Dermatol Res 296(12): 577-9.

Homberg M ,Magin TM (2014) Beyond expectations: novel insights into epidermal keratin function and regulation. Int Rev Cell Mol Biol 311: 265-306.

Hu J ,Ng PC (2013) SIFT Indel: predictions for the functional effects of amino acid insertions/deletions in proteins. PloS one 8(10): e77940.

Kim EN, Harris AG, Bingham LJ, Yan W, Su JC, Murrell DF (2017) A Review of 52 Pedigrees with Epidermolysis Bullosa Simplex Identifying Ten Novel Mutations in KRT5 and KRT14 in Australia. Acta Derm Venereol 97(9): 1114-1119.

Komori T, Dainichi T, Masuno Y, Otsuka A, Nakano H, Sawamura D, Ishida-Yamamoto A, Kabashima K (2018) p.Glu477Lys mutation in keratin 5 is not necessarily mortal in generalized severe epidermolysis bullosa simplex. J Dermatol 45(8): e209-e210.

Lalor L, Titeux M, Palisson F, Fuentes I, Yubero MJ, Tasanen K, Huilaja L, Has C, Tadini G, Haggstrom AN, Hovnanian A, Lucky AW (2019) Epidermolysis bullosa simplex-generalized severe type due to keratin 5 p.Glu477Lys mutation: Genotype-phenotype correlation and in silico modeling analysis. Pediatr Dermatol 36(1): 132-138.

Li H ,Durbin R (2009) Fast and accurate short read alignment with Burrows–Wheeler transform. bioinformatics 25(14): 1754-1760.

Müller FB, Anton-Lamprecht I, Küster W, Korge BP (1999) A premature stop codon mutation in the 2B helix termination peptide of keratin 5 in a German epidermolysis bullosa simplex Dowling-Meara case. J Invest Dermatol 112(6): 988-90.

Sathishkumar D, Orrin E, Terron-Kwiatkowski A, Browne F, Martinez AE, Mellerio JE, Ogboli M, Hoey S, Ozoemena L, Liu L, Baty D, McGrath JA, Moss C (2016) The p.Glu477Lys Mutation in Keratin 5 Is Strongly Associated with Mortality in Generalized Severe Epidermolysis Bullosa Simplex. J Invest Dermatol 136(3): 719-721.

Schumann H, Roth W, Has C, Volz A, Erfurt-Berge C, Magin TM, Bruckner-Tuderman L (2012) Verrucous carcinoma in epidermolysis bullosa simplex is possibly associated with a novel mutation in the keratin 5 gene. Br J Dermatol 167(4): 929-36.

Schwarz JM, Cooper DN, Schuelke M, Seelow D (2014) MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 11(4): 361-362.

Stephens K, Ehrlich P, Weaver M, Le R, Spencer A, Sybert VP (1997) Primers for exon-specific amplification of the KRT5 gene: identification of novel and recurrent mutations in epidermolysis bullosa simplex patients. J Invest Dermatol 108(3): 349-53.

Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38(16): e164.

Wertheim-Tysarowska K, Ołdak M, Giza A, Kutkowska-Kaźmierczak A, Sota J, Przybylska D, Woźniak K, Śniegórska D, Niepokój K, Sobczyńska-Tomaszewska A, Rygiel AM, Płoski R, Bal J, Kowalewski C (2016) Novel sporadic and recurrent mutations in KRT5 and KRT14 genes in Polish epidermolysis bullosa simplex patients: further insights into epidemiology and genotype-phenotype correlation. J Appl Genet 57(2): 175-81.

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Published

2021-08-02

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