Insertion of the IL1RAPL1 gene into the duplication junction of the dystrophin gene

Abstract

Duplications of one or more exons of the dystrophin gene are the second most common mutation in dystrophinopathies. Even though duplications are suggested to occur with greater complexity than thought earlier, they have been considered an intragenic event. Here, we report the insertion of a part of the IL1RAPL1 (interleukin-1 receptor accessory protein-like 1) gene into the duplication junction site. When the actual exon junction was examined in 15 duplication mutations in the dystrophin gene by analyzing dystrophin mRNA, one patient was found to have an unknown 621 bp insertion at the junction of duplication of exons from 56 to 62. Unexpectedly, the inserted sequence was found completely identical to sequences of exons 3-5 of the IL1RAPL1 gene that is nearly 100 kb distal from the dystrophin gene. Accordingly, the insertion of IL1RAPL1 exons 3-5 between dystrophin exons 62 and 56 was confirmed at the genomic sequence level. One junction between the IL1RAPL1 intron 5 and dystrophin intron 55 was localized within an Alu sequence. These results showed that a fragment of the IL1RAPL1 gene was inserted into the duplication junction of the dystrophin gene in the same direction as the dystrophin gene. This suggests the novel possibility of co-occurrence of complex genomic rearrangements in dystrophinopathy.

Novel SPTBN2 gene mutation and first intragenic deletion in early onset spinocerebellar ataxia type 5

“…18,19 The suggested minimum requirement for favorable homologous recombination is 75% of identity between Alu elements. 20,21 In our study, we hypothesize that the de novo deletion of 10895 bp in SPTBN2 gene was generated by an unequal homologous recombination event, due to a misalignment between Alu Sx in intron 12 (5ʹ deletion boundary) of SPTBN2 gene and Alu Sx in intron 20 (3ʹ deletion boundary). Both Alu Sx show 86% sequence identity (91% without gaps) and a microhomology domain of 50 bp.…”

“…These sequences of about 300 base pairs share a great level of identity and allow more efficient homologous recombination than sequences with an imperfect identity which would represent an inefficient target 18,19 . The suggested minimum requirement for favorable homologous recombination is 75% of identity between Alu elements 20,21 . In our study, we hypothesize that the de novo deletion of 10895 bp in SPTBN2 gene was generated by an unequal homologous recombination event, due to a misalignment between Alu Sx in intron 12 (5ʹ deletion boundary) of SPTBN2 gene and Alu Sx in intron 20 (3ʹ deletion boundary).…”

Genetic Counselling Pitfall: Co-Occurrence of an 11.8-Mb Xp22 Duplication and an Xp21.2 Duplication Disrupting IL1RAPL1

“…The 2 male patients of this family presenting with the same isolated intragenic IL1RAPL1 duplication (III.1and III.5) share a similar phenotype, including autism spectrum disorders, short attention span, and dyspraxia without ID as well as dysmorphic features. Froyen et al [2007] and Zhang et al [2009] both reported a case of IL1RAPL1 duplication associated with ID, but in both cases, the CNV encompassed other XLID genes such as CASK and DMD. Four patients in the DECIPHER database (274669, 277292, 249698 and 280583; https://decipher.sanger.ac.uk/) harbour an overlapping intragenic IL1RAPL1 duplication.…”

The X-linked intellectual disability protein IL1RAPL1 regulates excitatory synapse formation by binding PTPδ and RhoGAP2

“…(1), is associated with a non-syndromic form of mental retardation (MR). Similar to some other genes involved in cognitive impairment (2–4), IL1RAPL1 mutations are associated with a spectrum of cognitive impairments ranging from MR to autism (5–11). …”