A novel nonsense mutation in keratin 10 causes a familial case of recessive epidermolytic ichthyosis

Abstract

Epidermolytic ichthyosis (EI) is a rare skin disorder characterized by generalized erythroderma and cutaneous blistering at birth, which is substituted by hyperkeratosis later in life. It is caused by autosomal dominant mutations in highly conserved regions of KRT1 and KRT10. To date, only four mutations with autosomal recessive inheritance of EI have been described in consanguineous families. All of them affect the 2B domain of KRT10. In the present study, we describe four patients with EI (including one lethal case) born from unaffected parents in a consanguineous family of a native Venezuelan community. The objective of this study was to characterize the clinical, genetic, and morphological aspects of the disease in this family, as well as understand its functional implications. Genomic DNA was sequenced for KRT10 and KRT1. Immunofluoresence for keratin expression was performed on cutaneous biopsies. After examination of cutaneous biopsies histology, our results showed hyperkeratosis and acantholysis with an expanded granular layer. Sequencing of KRT10 demonstrated a nonsense mutation (p.Tyr282Ter.) corresponding to the 1B domain of the protein in patients and a heterozygous pattern in other family members, resulting in complete absence of K10. The loss of K10 was compensated by upregulation of K14 and K17. In conclusion, this novel mutation in KRT10 is the first recessive genetic variation that is not located in the so called “hot spot” for recessive EI, suggesting that other areas of the gene are also susceptible for such mutations.

Recessive epidermolytic ichthyosis results from loss of keratin 10 expression, regardless of the mutation location

“…In contrast to the previously described EI‐causing recessive mutations, which were all located within the gene region encoding the alpha‐helical rod domain, p.Tyr11Ter resides within a region encoding the head domain of K10 (Fig. c).…”

“…To date, only five recessive mutations have been shown to cause EI . Four of these were found to reside in close proximity in the 2B domain‐encoding part of the gene (Fig.…”

“…Four of these were found to reside in close proximity in the 2B domain‐encoding part of the gene (Fig. c), which has led some authors to designate this area as a ‘genetic hotspot’ for recessive EI, while a recent study identified a fifth mutation located in the 1B domain‐encoding part of the gene. Thus, the location of the causative mutation reported in the present study is exceptional, as it resides at the very beginning of the gene coding sequence.…”

“…To date, only five recessive KRT10 mutations have been shown to cause autosomal recessive EI, all of which have been found to lead to complete absence of the K10 protein . These mutations all reside within the gene region encoding the highly conserved alpha‐helical rod domain of K10.…”

Keratins and skin disease

“…There is a high level of clinical heterogeneity between conditions caused by mutations in KRT1, making phenotypic prediction more difficult than with KRT5/KRT14 mutations (Lane and McLean 2004). Recessive familial cases of EI have also been identified in consanguineous families due to nonsense mutations in KRT10 leading to loss of K10 (Gutierrez et al 2013).…”