A novel complex mutation in the LDL receptor gene probably caused by the simultaneous occurrence of deletion and insertion in the same region

Abstract

A novel complex mutation with the presence of both deletion and insertion in very close proximity in the same region was detected in exon 8 of the LDL receptor gene from two apparently unrelated Japanese families with familial hypercholesterolemia (FH). In this mutant LDL receptor gene, the nine bases from nucleotide (nt) 1115 to nt 1123 (AGGGTGGCT) were replaced by six different bases (CACTGA), and consequently the four amino acids from codon 351 to 354, Glu-Gly-Gly-Tyr, were replaced by three amino acids, Ala-Leu-Asn, in the conserved amino acid region of the growth factor repeat B of the LDL receptor. The nature of the amino acid substitution and data on the families suggest that this mutation is very likely to affect the LDL receptor function and cause FH. The generation of this complex mutation can be explained by the simultaneous occurrence of deletion and insertion through the formation of a hairpin-loop structure mediated by inverted repeat sequences. This this mutation supports the hypothesis that inverted repeat sequences influence the stability of a given gene and promote human gene mutations.

Genetic and clinical analysis in 10 Spanish patients with multiple endocrine neoplasia type 1

“…A similar (Figure 1), located in exon 4, could be explained by the formation of a hairpin loop structure (Figure 2) as has been already described in other diseases. 15 There are several inverted repeated sequences around the region in which the mutation is located. To generate this complex mutation, these inverted repeated sequences could have formed a hairpin loop structure during replication and both the deletion and the insertion could have occurred within this structure.…”

Fabry Disease: Thirty-Five Mutations in the α-Galactosidase A Gene in Patients with Classic and Variant Phenotypes

“…Previously, complex mutations were identified in several genes, including the LDL receptor gene (23), the HPRT gene (24), and the serum cholinesterase gene (25). Various mechanisms have been proposed for the generation of these mutations, including gene conversion between evolutionarily related sequences (26), or misalignment of "quasi-palindromic" sequences during DNA replication and the subsequent deletion or insertion of bases that might serve to stabilize a hairpin loop (27).…”

Mutation Screening of the Low-Density Lipoprotein Receptor Gene in Japanese Patients with Familial Hypercholesterolemia from the Kanto Area

“…These were lower than reported in previous studies by Yu et al (41.5%) in the Hokuriku area and by Maruyama et al in the Kansai area (31.7%), and thus the detection rate obtained using our strategy may be less than satisfactory. In Japan, numerous additional mutations, including large deletions, have been reported [17][18][19][20][21][22][23] Another report also indicated a lower prevalence of 7 mutations (different from those we identified) in LDL-R genes from 44 of 101 Japanese FH patients of unknown origins using single-strand conformation polymorphism (SSCP) analysis24). The Japanese are generally believed to be a genetically uniracial population due to their prolonged geographical and political isolation.…”