Velho Renata Voltolini, Ludwig Nataniel Floriano, Alegra Taciane, Sperb-Ludwig Fernanda, Guarany Nicole Ruas, Matte Ursula, Schwartz Ida V D
Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, Porto Alegre, RS, Brazil.
Postgraduation Program on Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Avenida Bento Gonçalves, Porto Alegre, RS, Brazil.
J Hum Genet. 2016 Jun;61(6):555-60. doi: 10.1038/jhg.2016.13. Epub 2016 Mar 3.
Mucolipidosis (ML) III gamma is a rare autosomal-recessive disorder caused by pathogenic mutations in the GNPTG gene. GNPTG encodes the γ-subunit of GlcNAc-1-phosphotransferase that catalyzes mannose 6-phosphate targeting signal synthesis on soluble lysosomal enzymes. ML III gamma patients are characterized by missorting of lysosomal enzymes. In this report, we describe the probable occurrence of mRNA editing in two ML III gamma patients. Patients A and B (siblings) presented at the adult age with a typical clinical picture of ML III gamma, mainly compromising bone and joints, and high levels of lysosomal enzymes in plasma and low levels in fibroblasts. Both were found to be homozygous for c.-112C>G and c.328G>T (p.Glu110Ter) mutations in genomic DNA (gDNA) analysis of GNPTG. Analysis of complementary DNA (cDNA), however, showed normal genotypes for both patients. Low GNPTG mRNA expression was observed in both patients. The mRNA editing can explain the differences found in patients A and B regarding gDNA and cDNA analysis, and the mild clinical phenotype associated with homozygosity for a nonsense mutation. Our results suggest that mRNA editing can be more frequent than expected in monogenic disorders and that GNPTG analysis should be performed on gDNA.
黏脂贮积症（ML）III型γ是一种罕见的常染色体隐性疾病，由GNPTG基因的致病性突变引起。GNPTG编码N-乙酰葡糖胺-1-磷酸转移酶的γ亚基，该酶催化可溶性溶酶体酶上的甘露糖6-磷酸靶向信号合成。ML III型γ患者的特征是溶酶体酶分选错误。在本报告中，我们描述了两名ML III型γ患者中可能发生的mRNA编辑情况。患者A和B（兄弟姐妹）成年后出现典型的ML III型γ临床表现，主要累及骨骼和关节，血浆中溶酶体酶水平高，成纤维细胞中水平低。在GNPTG的基因组DNA（gDNA）分析中，两人均被发现为c.-112C>G和c.328G>T（p.Glu110Ter）突变的纯合子。然而，互补DNA（cDNA）分析显示两名患者的基因型均正常。两名患者均观察到低水平的GNPTG mRNA表达。mRNA编辑可以解释患者A和B在gDNA和cDNA分析中发现的差异，以及与无义突变纯合性相关的轻度临床表型。我们的结果表明，mRNA编辑在单基因疾病中可能比预期更频繁，并且应在gDNA上进行GNPTG分析。
