Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA

Abstract

Background-Autosomal recessive congenital ichthyosis (ARCI) is a rare hereditary disorder of cornification. Mutations in the transglutaminase-1 (TGM1) gene, which encodes for the epidermal enzyme transglutaminase-1 (TGase-1), are one of the causes of ARCI.

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

“…Patients who had at least one mutation predicted to truncate TGase-1 were more likely to have severe hypohidrosis and overheating than those with TGM1 missense mutations only. 35 Clinically other minor ARCI variants/subtypes can be distinguished: bathing suit ichthyosis 47 has been attributed to particular TGM1 mutations that render the enzyme sensitive to ambient temperature (Fig 2, I ). 32,42,43,48 The self-healing collodion baby representing approximately 10% of all ARCI cases 36,49 has so far been associated with TGM1 or ALOX12B mutations.…”

“…6,35,46,[229][230][231][232] Importantly, clinicians have to consider the functional consequences of the epidermal barrier defect, such as increased risk of systemic absorption and toxicity, especially in infants. [231][232][233] Neonates with severe congenital phenotypes may require intensive care using humidified isolettes (incubators) to avoid temperature instability and hypernatremic dehydration, and observation for signs of cutaneous infection and septicemia.…”

Regulation of the activities of the mammalian transglutaminase family of enzymes

“…Although most mutations await biochemical characterization to establish whether their effects are due to destabilization of the protein or altering regulatory sites, they effectively lead to reduced TG1 cross-linking activity during keratinocyte maturation. 62 …”

NIPAL4 mutation c.527C˃A identified in Romanian patients with autosomal recessive congenital ichthyosis

“…Of these, palmoplantar keratoderma is a constant feature of ARCI patients with NIPAL4 mutations, while the yellowish hue and absence of hyperlinearity are considered highly suggestive of the presence of a NIPAL4 mutation (12). Anhidrosis or hypohidrosis is one of the most troublesome problems for ARCI patients, as it might associate heat intolerance, fatigue and erythroderma aggravation when in a hot environment (8).Two of our patients (P1 and P2) presented this symptom, which seems to be a frequent find in patients with NIPAL4 mutations, or mutations of TGM 1, ALOX12B, and ALOXE3, and in some cases requires retinoid therapy (15)(16)(17). Given that anhidrosis is frequently seen in mild cases of ichthyosis, where it might show a tendency for self-improving, it is considered that gland suppression is not related to the degree of disease severity (18).…”