摘要
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 indi viduals, defective cornified envelopes (CEs) have been reported by light or elec tron microscopic examination in epidermal scale, nail and/or hair. These finding s suggest that assessment of such defects could have a diagnostic utility in dis tinguishing TGM1-deficient versus non-deficient cases of autosomal recessive i chthyosis (ARI) . Present work (a) examines the integrity of CEs in epidermal sc ale 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 w hich 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 electronmi croscopy. Both epidermal scale and nail from the index case lacked the prominent cell borders that were visible by phase contrast microscopy after detergent ext raction of control samples. (By contrast, abundant envelope structures were visi ble in extracted epidermal scale from patients with ichthyosis vulgaris, loricri n keratoderma and epidermolytic hyperkeratosis.) Electronmicroscopy confirmed th e paucity of intact CEs, and revealed further that hair cuticle cells from the s ame subject also lacked the marginal bands that are visible in control hair samp les. Such aberrations were evident neither in the samples from asymptomatic rela tives of the index case nor in the hair-cuticle cells of numerous normal indivi duals, evidence that this defect is not a common polymorphism. These studies ext end 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 heterozy gous mutation in TGM1 in combination with an inactive allele, confers a cross-l inking deficiency in a variety of keratinizing epithelia, as previously shown fo r TGM1-negative LI. These results further suggest that a non-invasive assessme nt of scale, nail and hair could be of diagnostic utility in distinguishing pati ents across a full range of phenotypes with deficiency in TGM1-encoded transglu taminase activity from other causes of ARI.
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 indi viduals, defective cornified envelopes (CEs) have been reported by light or elec tron microscopic examination in epidermal scale, nail and/or hair. These finding s suggest that assessment of such defects could have a diagnostic utility in dis tinguishing TGM1-deficient versus non-deficient cases of autosomal recessive i chthyosis (ARI) . Present work (a) examines the integrity of CEs in epidermal sc ale 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 w hich 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 electronmi croscopy. Both epidermal scale and nail from the index case lacked the prominent cell borders that were visible by phase contrast microscopy after detergent ext raction of control samples. (By contrast, abundant envelope structures were visi ble in extracted epidermal scale from patients with ichthyosis vulgaris, loricri n keratoderma and epidermolytic hyperkeratosis.) Electronmicroscopy confirmed th e paucity of intact CEs, and revealed further that hair cuticle cells from the s ame subject also lacked the marginal bands that are visible in control hair samp les. Such aberrations were evident neither in the samples from asymptomatic rela tives of the index case nor in the hair-cuticle cells of numerous normal indivi duals, evidence that this defect is not a common polymorphism. These studies ext end 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 heterozy gous mutation in TGM1 in combination with an inactive allele, confers a cross-l inking deficiency in a variety of keratinizing epithelia, as previously shown fo r TGM1-negative LI. These results further suggest that a non-invasive assessme nt of scale, nail and hair could be of diagnostic utility in distinguishing pati ents across a full range of phenotypes with deficiency in TGM1-encoded transglu taminase activity from other causes of ARI.
