Structural changes in epidermal scale and appendages as indicators of defective TGM1 activity

Defective transglutaminase 1 (TGM1) is a causative factor in some cases of lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE) despite large differences in the phenotype between these conditions. In some of these individuals, defective cornified envelopes (CEs) have been reported by light or electron microscopic examination in epidermal scale, nail and/or hair. These findings suggest that assessment of such defects could have a diagnostic utility in distinguishing TG1-deficient versus non-deficient cases of autosomal recessive ichthyosis (ARI) . Present work (a) examines the integrity of CEs in epidermal scale and appendages in a case of TGM1-deficient CIE, (b) assesses the utility of hair/nail versus scale analysis in the diagnosis of TGM1 deficiency in vivo and (c) helps characterize the consequences of the V518M mutation in TGM1, about which conflicting reports have appeared. To this end, epidermal scale or callus, nail and hair samples from a patient with TGM1-deficient CIE, his asymptomatic family members and control subjects were extracted vigorously in sodium dodecyl sulfate and dithiothreitol and examined by light (phase contrast) and electron microscopy. Both epidermal scale and nail from the index case lacked the prominent cell borders that were visible by phase contrast microscopy after detergent extraction of control samples. (By contrast, abundant envelope structures were visible in extracted epidermal scale from patients with ichthyosis vulgaris, loricrin keratoderma and epidermolytic hyperkeratosis.) Electron microscopy confirmed the paucity of intact CEs, and revealed further that hair cuticle cells from the same subject also lacked the marginal bands that are visible in control hair samples. Such aberrations were evident neither in the samples from asymptomatic relatives of the index case nor in the hair-cuticle cells of numerous normal individuals, evidence that this defect is not a common polymorphism. These studies extend our prior work on TGM1-deficient LI to the full spectrum of TGM1-deficient patients, showing that the CIE phenotype, when attributable to a V518M heterozygous mutation in TGM1 in combination with an inactive allele, confers a cross-linking deficiency in a variety of keratinizing epithelia, as previously shown for TGM1-negative LI. These results further suggest that a non-invasive assessment of scale, nail and hair could be of diagnostic utility in distinguishing patients across a full range of phenotypes with deficiency in TGM1-encoded transglutaminase activity from other causes of ARI.