Bichakjian C K, Nair R P, Wu W W, Goldberg S, Elder J T
Department of Dermatology, University of Michigan, Ann Arbor 48105-0932, USA.
J Invest Dermatol. 1998 Feb;110(2):179-82. doi: 10.1046/j.1523-1747.1998.00104.x.
Lamellar ichthyosis is a severe, generalized, autosomal recessive genodermatosis characterized clinically by large, parchment-like scales and histologically by acanthosis and marked hyperkeratosis. Genetic heterogeneity in lamellar ichthyosis has been recognized with reports of two linked loci (on chromosomes 14q11 and 2q33-35). In a cohort of four small families with lamellar ichthyosis we found confirmatory evidence for linkage (p < or = 0.01) to D14S275, a microsatellite marker close to transglutaminase 1 on chromosome 14q11. We also identified two novel transglutaminase 1 mutations in an affected sibling pair from one of these families. The paternal mutation in exon 3, 1387insCAGC, causes a frameshift predicted to result in premature termination of translation within the same exon. The maternal mutation in exon 8, 4561delAC, also causes a frameshift and a premature stop codon in this exon. The mother of these siblings recently became pregnant with twins. Genotyping and direct sequencing of DNA isolated from fetal amniotic fluid cultures revealed the presence of the paternal but the absence of the maternal mutation, thus predicting a normal skin phenotype. Both twins were born with normal-appearing skin. Our findings demonstrate that mutations of both alleles of the transglutaminase 1 gene are the cause of lamellar ichthyosis in this family, and illustrate an emerging clinical application of molecular genetics in dermatology.
板层状鱼鳞病是一种严重的、全身性的常染色体隐性遗传性皮肤病，临床特征为大片状、羊皮纸样鳞屑，组织学表现为棘层肥厚和显著的角化过度。随着两个连锁基因座（位于14号染色体q11和2号染色体q33 - 35）报道的出现，板层状鱼鳞病的遗传异质性已得到确认。在一个由四个小板层状鱼鳞病家族组成的队列中，我们发现了与D14S275连锁的证实性证据（p≤0.01），D14S275是一个靠近14号染色体q11上转谷氨酰胺酶1的微卫星标记。我们还在其中一个家族的一对患病同胞中鉴定出两个新的转谷氨酰胺酶1突变。外显子3中的父系突变1387insCAGC导致移码，预计会导致同一外显子内翻译提前终止。外显子8中的母系突变4561delAC也导致移码，并在该外显子中产生提前终止密码子。这些同胞的母亲最近怀了双胞胎。对从胎儿羊水培养物中分离的DNA进行基因分型和直接测序，结果显示存在父系突变但不存在母系突变，因此预测皮肤表型正常。两个双胞胎出生时皮肤外观正常。我们的研究结果表明，转谷氨酰胺酶1基因的两个等位基因的突变是该家族板层状鱼鳞病的病因，并说明了分子遗传学在皮肤病学中正在出现的临床应用。
