Monoallelic Mutations in the Translation Initiation Codon of KLHL24 Cause Skin Fragility

Am J Hum Genet. 2016 Dec 1;99(6):1395-1404. doi: 10.1016/j.ajhg.2016.11.005.

Yinghong He ¹, Kristin Maier ¹, Juna Leppert ¹, Ingrid Hausser ², Agnes Schwieger-Briel ³, Lisa Weibel ³, Martin Theiler ³, Dimitra Kiritsi ¹, Hauke Busch ⁴, Melanie Boerries ⁴, Katariina Hannula-Jouppi ⁵, Hannele Heikkilä ⁶, Kaisa Tasanen ⁷, Daniele Castiglia ⁸, Giovanna Zambruno ⁹, Cristina Has ¹⁰

Affiliations

1 Department of Dermatology, University Medical Center Freiburg, Freiburg 79104, Germany.
2 Department of Pathology, University of Heidelberg, Heidelberg 69120, Germany.
3 Department of Paediatric Dermatology, University Children's Hospital Zurich, Zurich 8091, Switzerland; Department of Dermatology, University Hospital Zurich, Zurich 8091, Switzerland.
4 Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg 79104, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Comprehensive Cancer Center Freiburg, Freiburg 79106, Germany.
5 Department of Dermatology and Allergology, University of Helsinki and Helsinki University Hospital, Helsinki 00014, Finland; Folkhälsan Institute of Genetics, University of Helsinki, Helsinki 00014, Finland.
6 Department of Dermatology and Allergology, University of Helsinki and Helsinki University Hospital, Helsinki 00014, Finland.
7 Department of Dermatology, PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu 90014, Finland.
8 Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Rome 00167, Italy.
9 Genetic and Rare Diseases Research Area, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome 00165, Italy.
10 Department of Dermatology, University Medical Center Freiburg, Freiburg 79104, Germany. Electronic address: cristina.has@uniklinik-freiburg.de.

PMID: 27889062 DOI: 10.1016/j.ajhg.2016.11.005

Abstract

The genetic basis of epidermolysis bullosa, a group of genetic disorders characterized by the mechanically induced formation of skin blisters, is largely known, but a number of cases still remain genetically unsolved. Here, we used whole-exome and targeted Sequencing to identify monoallelic mutations, c.1A>G and c.2T>C, in the translation initiation codon of the gene encoding kelch-like protein 24 (KLHL24) in 14 individuals with a distinct skin-fragility phenotype and skin cleavage within basal keratinocytes. Remarkably, mutation c.1A>G occurred de novo and was recurrent in families originating from different countries. The striking similarities of the clinical features of the affected individuals point to a unique and very specific pathomechanism. We showed that mutations in the translation initiation codon of KLHL24 lead to the usage of a downstream translation initiation site with the same reading frame and formation of a truncated polypeptide. The pathobiology was examined in keratinocytes and fibroblasts of the affected individuals and via expression of mutant KLHL24, and we found mutant KLHL24 to be associated with abnormalities of intermediate filaments in keratinocytes and fibroblasts. In particular, KLHL24 mutations were associated with irregular and fragmented keratin 14. Recombinant overexpression of normal KLHL24 promoted keratin 14 degradation, whereas mutant KLHL24 showed less activity than the normal molecule. These findings identify KLHL24 mutations as a cause of skin fragility and identify a role for KLHL24 in maintaining the balance between intermediate filament stability and degradation required for skin integrity.

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