A novel complex deletion-insertion mutation mediated by Alu repetitive elements leads to lipoprotein lipase deficiency.
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 150bp 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.
Okubo
Minoru
M
Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan. QFG00550@nifty.com
Horinishi
Asako
A
Saito
Mieko
M
Ebara
Tetsu
T
Endo
Yoriko
Y
Kaku
Kohei
K
Murase
Toshio
T
Eto
Masaaki
M
D000208:Acute Disease; D000328:Adult; D020087:Alu Elements / Q000235:genetics*; D001483:Base Sequence; D015139:Blotting, Southern; D004251:DNA Transposable Elements / Q000235:genetics; D005260:Female; D006801:Humans; D008071:Lipoprotein Lipase / Q000172:deficiency* / Q000235:genetics*; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010195:Pancreatitis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D017384:Sequence Deletion; D012689:Sequence Homology, Nucleic Acid
D004251:DNA Transposable Elements; D012333:RNA, Messenger; D008071:Lipoprotein Lipase