Identification of an Interstitial 18p11.32-p11.31 Duplication Including the EMILIN2 Gene in a Family with Porokeratosis of Mibelli

Abstract

Porokeratosis is a rare disease of epidermal keratinization characterized by the histopathological feature of the cornoid lamella, a column of tightly fitted parakeratocytic cells, whose etiology is still unclear. Porokeratosis of Mibelli is a subtype of porokeratosis presenting a single plaque or a small number of plaques of variable size located unilaterally on limbs. It frequently appears in childhood and occurs with a higher incidence in males. Cytogenetic analyses were performed in all members of the family on lesioned and uninvolved skin. An array-CGH analysis was also performed utilizing the Human Genome CGH Microarray Kit G3 400 with 5.3 KB overall median probe spacing. Gene expression was performed on skin fibroblasts. In this study, we describe a Caucasian healthy 4-year-old child and his father showing features of porokeratosis of Mibelli. Array-CGH analysis revealed an interstitial 429.5 Kb duplication of chromosome 18p11.32-p11.3 containing four genes, namely: SMCHD1, EMILIN2, LPIN2, and MYOM1 both in patient and his father. EMILIN2 resulted overexpressed on skin fibroblasts. Also other members of this family, without evident signs of porokeratosis, carried the same duplication. Among these genes, we focused our attention on elastin microfibril interfacer 2 (EMILIN2) gene. Apoptosis plays a fundamental role in maintaining epidermal homeostasis, balancing keratinocytes proliferation, and forming the stratum corneum. EMILIN2 is known to trigger the apoptosis of different cell lines negatively affecting cell survival. It is expressed in the skin. We could speculate that the duplication and overexpression of EMILIN2 cause an abnormal apoptosis of epidermal keratinocytes and alter the process of keratinization, even if other epigenetic and genetic factors could also be involved. Our results could contribute to a better understanding of the pathogenesis of porokeratosis of Mibelli.

Inherited duplication of the short arm of chromosome 18p11.32–p11.31 associated with developmental delay/intellectual disability

“…Ocella et al (2013) report a family with a pure duplication of 18p11.32-p11.31 that includes SMCHD1, EMILIN2, LPIN2 and MYOM1 in a father and son with isolated porokeratosis of Mibelli; other members of this family carry the duplication without any clinical phenotype and the authors suggest that overexpression of EMILIN2 and an interaction between genetic factors or differential environmental exposure is causative of porokeratosis of Mibelli and the variable expression in this family. Kashevarova et al (2014) report a boy with a pure duplication of 18p11.32 that includes SMCHD1, METTL4 and NDC80.…”

“…with motor stereotypy, dysarthria, aggression, attention deficit hyperactivity disorder, autism and some dysmorphism with a duplication of 18p11.32 (Ocella et al, 2013;Kashevarova et al, 2014). Of the reported cases, it is important to note that only Ocella et al (2013) and Kashevarova et al (2014) use array CGH for characterization of the breakpoints.…”

“…Of the reported cases, it is important to note that only Ocella et al (2013) and Kashevarova et al (2014) use array CGH for characterization of the breakpoints.…”

“…In general, pathogenic duplications are less prevalent than deletions in clinically ascertained samples (except for the X chromosome); they usually confer milder phenotypes than the reciprocal deletions, most are inherited from one parent, and the vast majority are tandem (head-to-tail) in orientation (Vissers et al, 2009;Stankiewicz et al, 2010). Pure 18p trisomy is reported rarely (Taylor et al, 1975;Takeda et al, 1989;Wolff et al, 1991;Moog et al, 1994;Li et al, 1998;Marical et al, 2007;Ocella et al, 2013;Kashevarova et al, 2014). These patients have a variable phenotype ranging from normal to mild.…”

A 18p11.23-p11.31 microduplication in a boy with psychomotor delay, cerebellar vermis hypoplasia, chorioretinal coloboma, deafness and GH deficiency

“…An 18p11.31-p11.32 duplication of 429.5 Kb, including four genes, among which the likely causative EMILIN2 , has been identified in a family with porokeratosis of Mibelli [6]. In the same region, other authors [7] detected a larger overlapping 2.6 Mb microduplication involving at least nine genes in two siblings with variable levels of intellectual disability/developmental delay and behavioral difficulties.…”