Molecular Analysis of 250 Patients with Autosomal Recessive Congenital Ichthyosis: Evidence for Mutation Hotspots in ALOXE3 and Allelic Heterogeneity in ALOX12B

Abstract

In recent years several new genes for autosomal recessive congenital ichthyosis (ARCI) have been identified. However, little is known about the molecular epidemiology and pathophysiology of this genetically and clinically heterogeneous group of severe disorders of keratinization. ARCI is characterized by intense scaling of the whole integument often associated with erythema. We and others have shown that mutations in ALOX12B and ALOXE3, coding for the lipoxygenases 12R-LOX and eLOX-3 predominantly synthesized in the epidermis, can underlie this rare condition. Here we have surveyed a large group of 250 patients with ARCI for mutations in these two genes. We have identified 11 different previously unreported mutations in ALOX12B and ALOXE3 in 21 ARCI patients from 19 unrelated families and demonstrated that mutations in the two genes are the second most common cause for ARCI in this cohort of patients. Examination of the molecular data revealed allelic heterogeneity for ALOX12B and two mutational hotspots in ALOXE3. Functional analysis of all missense mutations and a splice site mutation demonstrated that complete loss of function of the enzymes underlies the phenotype. Our findings further establish the pivotal role of the 12-lipoxygenase pathway during epidermal differentiation.

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…26 A large cohort of 520 affected families showed a mutation distribution of 32% for TGM1, 16% for NIPAL4, 12% for ALOX12B, 8% for CYP4F22, 5% for ALOXE3, and 5% for ABCA12, 27 which approximately correlated with a recent report of 250 patients. 28 At least 22% of these cases did not exhibit mutations in any of the known ARCI genes, 27 implying that further loci must exist, such as two loci on chromosome 12p11.2-q13. 29,30 A preliminary clinicogenetic correlation based on the [17][18][19][20] and our discussions at the consensus conference is given in Tables II and III. LI is characterized by coarse and brown/dark scaling (Fig 2, E and F ).…”

Inherited ichthyoses/generalized Mendelian disorders of cornification

“…The majority of the congenital phenotypes transform into generalized scaling that typically persists throughout life. 30,31 Polyhydramnion associated with prematurity and post-natal failure to thrive are clinical features relevant for the diagnosis of ichthyosis-prematurity syndrome (FATP4). 32 KI (KRT1, KRT2 and KRT10; in its generalized form also called epidermolytic ichthyosis, bullous ichthyosis, bullous CIE Brocq or ichthyosis bullosa of Siemens) presents with generalized blistering at birth that later transforms into hyperkeratosis (Figure 1d).…”

Case report of adolescent male with non-bullous congenital ichthyosiform erythroderma visiting dermatology clinic of King Fahad Military Hospital, Jeddah, Saudi Arabia, 2017

“…5 Non bullous congenital ichthyosiform erythroderma (NBCIE) is a rare with skin abnormalities tend to be less severe than those in harlequin ichthyosis. 6 NBCIE is an autosomal recessive ichthyosis, which occurs in 1 in 300,000 births. 7 NBCIE, appears as generalized erythroderma with fine white scales that gradually replace the collodion membrane.…”