A novel complex deletion–insertion mutation mediated by Alu repetitive elements leads to lipoprotein lipase deficiency

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• 作者：Minoru Okubo ; Asako Horinishi ; Mieko Saito ; Tetsu Ebara ; Yoriko Endo ; Kohei Kaku ; Toshio Murase ; Masaaki Eto
• 关键词：Lipoprotein lipase ; LPL ; LPL deficiency ; Chylomicronemia ; Alu repetitive element ; Retrotransposition ; Complex deletion– ; insertion
• 刊名：Molecular Genetics and Metabolism
• 出版年：2007
• 期刊代码：175_10967192
• 类别：bio
• 出版时间：November 2007
• 卷：92
• 期：3
• 页码：229-233
• 文件大小：420 K

摘要

Lipoprotein lipase (LPL) deficiency is a rare autosomal recessive inherited disorder, characterized by marked hypertriglyceridemia, eruptive xanthoma, hepatosplenomegaly, recurrent attacks of pancreatitis, and markedly low or absent LPL activity in postheparin plasma. A majority of LPL deficient patients have been reported to have point mutations in the LPL gene; however, we find a complex deletion–insertion mutation by Alu elements, mobile retrotransposons, in a patient with LPL deficiency. This patient suffered from acute pancreatitis, showed chylomicronemia and lacked detectable LPL activity or mass in her postheparin plasma. Southern blot analysis and long-range PCR of the patient’s DNA demonstrated a 2.2-kb deletion encompassing exon 2. Sequence analysis revealed (1) a 2.3-kb deletion between an AT-rich region adjacent to an Alu element in intron 1 and another Alu element in intron 2; (2) an insertion of approximately 150 bp 5′-truncated Alu sequence with a poly (A) tail at the deletion point. The inserted sequence belongs to Alu Yb9, the youngest subfamily of Alu elements. The deletion occurred at the consensus cleavage site (3′-A|TTTT-5′) without target site duplication. These findings indicated that Alu retrotransposition caused the complex deletion–insertion. The patient was homozygous for this complex mutation, which eliminates exon 2 and leads to LPL deficiency. To our knowledge, the patient is the first case with LPL deficiency due to a complex deletion–insertion mediated by Alu repetitive elements.