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

Okubo, Minoru; Horinishi, Asako; Saito, Mieko; Ebara, Tetsu; Endo, Yoriko; Kaku, Kohei; Murase, Toshio; Eto, Masashi

doi:10.1016/j.ymgme.2007.06.018

Cited by 43 publications

(24 citation statements)

References 16 publications

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“…[5][6][7][8][9][10] Although we cannot completely rule out the possibility of two independent two-step events, we suggest that both aberrations can be traced back to a shared primary Alu retrotransposition event. This interpretation is based on (i) identity of the region harboring the presumed integration; (ii) involvement of AluYb8 as one of the most active Alu subfamilies; 16 (iii) presence of a classical L1-endonuclease site; 16 (iv) the sequence representing the potential target site duplication to be of the typical size of 16 bp; 16 and (v) the rarity of the haplotype on which both variants reside.…”

Section: Discussionmentioning

confidence: 64%

“…4 Meanwhile, a few disease-associated deletions that harbor Aluderived sequence insertions have been reported, including in the BRCA-1, CHD7, NF1, PMM2, GLA, and LPL genes. [5][6][7][8][9][10] Mechanistic interpretations referred to the one-step AMD concept, 8 or alternatively suggested a two-step scenario in which an Alu insertion precedes the actual deletion event. 10 The present study reports on the characterization of two distinct Alu insertion-associated deletions in the SPAST gene, alterations of which cause hereditary spastic paraplegia type SPG4 (OMIM 604277).…”

Section: Introductionmentioning

confidence: 99%

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A polymorphic Alu insertion that mediates distinct disease-associated deletions

et al. 2016

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Large deletions that are associated with insertions of Alu-derived sequence represent a rare, but potentially unique class of alterations. Whether they form by a one-step mechanism or by a primary insertion step followed by an independent secondary deletion step is not clear. We resolved two disease-associated SPAST deletions, which involve distinct exons by long range PCR. Alu-derived sequence was observed between the breakpoints in both cases. The intronic regions that represent the targets of potentially involved Alu retrotransposition events overlapped. Microsatellite-and SNP-based haplotyping indicated that both deletions originated on one and the same founder allele. Our data suggest that the deletions are best explained by two-step insertion-deletion scenarios for which a single Alu retrotransposition event represents the shared primary step. This Alu then mediated one of the deletions by non-homologous end joining and the other by non-allelic homologous recombination. Our findings thus strongly argue for temporal separation of insertion and deletion in Alu insertion-associated deletions. They also suggest that certain Alu integrations confer a general increase in local genomic instability, and that this explains why they are usually not detected during the probably short time that precedes the rearrangements they mediate.

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Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

A polymorphic Alu insertion that mediates distinct disease-associated deletions

et al. 2016

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“…However, RT-PCR did not detect any fragments from patient 1, suggesting that neither authentic nor cryptic splicing occurred and that there were no detectable AGL mRNA due to the deletion. Some of the large deletions were caused by Alu repetitive elements mediated recombination, as we described previously (23), but this was not the case in patient 1. In this patient, no repetitive elements were identified around the junction.…”

Section: Discussionmentioning

confidence: 49%

Egyptian glycogen storage disease type III – identification of six novel AGL mutations, including a large 1.5 kb deletion and a missense mutation p.L620P with subtype IIId

Endo¹,

Fateen²,

Shabrawy³

et al. 2009

Clinical Chemistry and Laboratory Medicine

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Background: Glycogen storage disease type III (GSD III) is caused by mutations in AGL which encodes for a single protein with two enzyme activities: oligo-1, 4-1, 4-glucantransferase (transferase) and amylo-1, 6-glucosidase. Activity of both enzymes is lost in most patients with GSD III, but in the very rare subtype IIId, transferase activity is deficient. Since the spectrum of AGL mutations is dependent on the ethnic group, we investigated the clinical and molecular characteristics in Egyptian patients with GSD III. Methods: Clinical features were examined in five Egyptian patients. AGL was sequenced and AGL haplotypes were determined. Results: Six novel AGL mutations were identified: a large deletion (c.3481-3588q1417del1525 bp), two insertions (c.1389insG and c.2368insA), two small deletions (c.2223-2224delGT and c.4041delT), and a missense mutation (p.L620P). p.L620P was found in a patient with IIId. Each mutation was located on a different AGL haplotype. Conclusions: Our results suggest that there is allelic and phenotypic heterogeneity of GSD III in Egypt. This is the second description of a large deletion in AGL. p.L620P is the second mutation found in GSD IIId.

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“…Laboratory tests including liver function tests, glucose, renal function, thyroid stimulating hormone and urine protein should be obtained to rule out secondary causes of HTG 103 . Specific tests documenting LPL or Apo C-II deficiency should be obtained if type I hyperlipidemia is suspected [104][105][106][107] . No standard treatment guidelines yet exist in the specific treatment of HTGP although a rational treatment strategy should include rapidly lowering serum TG, blocking the induction of pro-inflammatory mediators that lead to pancreatic destruction and reducing the likelihood of recurrence by eliminating offending agents, as is possible, and through the use of antihyperlipidemic medications [108][109][110][111] .…”

Section: Treatmentmentioning

confidence: 99%