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目的:探讨1个先天性常染色体隐性遗传性鱼鳞病家系的遗传学病因。方法:对1例火棉胶样婴儿进行全外显子组测序，Sanger测序验证基因变异位点。应用PolyPhen-2、PROVEAN和Mutation Taster软件以及蛋白同源建模方法预测基因变异的性质；实时荧光定量PCR和Western印迹法分析变异对等位基因mRNA与蛋白表达量的影响。结果:全外显子组测序与Sanger验证结果证实患儿n TGM1基因第6外显子存在c.919C>T（p.Arg307Trp）变异，第7外显子存在c.1019G>A（p.Gly340Glu）变异，且两变异等位基因分别遗传自其母亲与父亲。生物信息学预测提示两种变异均对蛋白结构有害，蛋白同源建模结果进一步证实上述结论。体外实验显示转染野生型质粒与转染c.919C>T或c.1019G>A突变型质粒的293T细胞n TGM1基因mRNA表达量差异无统计学意义（n t值分别为1.97、1.28，n P值分别为0.12、0.27），但转染突变型TGM1质粒的细胞TGase1蛋白含量显著下降。n 结论:TGM1基因c.919C>T与c.1019G>A变异可能是该严重鱼鳞病患儿的分子遗传学病因，其编码的错义氨基酸可能通过破坏TGase1蛋白结构，从而影响蛋白功能。n “,”Objective:To investigate the genetic etiology of a pedigree with autosomal recessive congenital ichthyosis.Methods:Whole-exome sequencing was performed in a collodion baby, and Sanger sequencing was conducted to verify gene mutations. The PolyPhen-2, PROVEAN and Mutation Taster softwares, as well as protein homology modeling methods, were used to predict effects of gene variants; real-time fluorescence-based quantitative PCR and Western blot analysis were performed to analyze the effect of mutations on allelic mRNA and protein expression.Results:Whole-exome sequencing and Sanger sequencing confirmed a mutation c.919C>T (p.Arg307Trp) in exon 6 and a mutation c.1019G>A (p.Gly340Glu) in exon 7 of then TGM1 gene in the infant, which were inherited from his mother and father respectively. Bioinformatics analysis suggested that both the two mutations were harmful to protein structures, which were further supported by protein homology modeling. n In vitro experiments showed that there was no significant difference in the mRNA expression of the n TGM1 gene between the 293T cells transfected with wild-type plasmids and those transfected with mutant plasmids containing the mutation c.919C>T or c.1019G>A (n t=1.97, 1.28, n P=0.12, 0.27, respectively) , but the TGase1 protein expression significantly decreased in the 293T cells transfected with the mutant n TGM1 plasmids.n Conclusion:The mutations c.919C>T and c.1019G>A in then TGM1 gene may be the molecular genetic etiology of severe ichthyosis in the infant, and the missense amino acids encoded by the two mutations may affect the TGase1 protein function by destroying its structure.n