Novel SLC7A7 large rearrangements in lysinuric protein intolerance patients involving the same AluY repeat

Abstract

Lysinuric protein intolerance (LPI) is a rare autosomal inherited disease caused by defective cationic aminoacid transport 4F2hc/y þ LAT-1 at the basolateral membrane of epithelial cells in the intestine and kidney. LPI is a multisystemic disease with a variety of clinical symptoms such as hepatosplenomegaly, osteoporosis, hypotonia, developmental delay, pulmonary insufficiency or end-stage renal disease. The SLC7A7 gene, which encodes the y þ LAT-1 protein, is mutated in LPI patients. Mutation analysis of the promoter localized in intron 1 and all exons of the SLC7A7 gene was performed in 11 patients from 9 unrelated LPI families. Point mutation screening was performed by exon direct sequencing and a new multiplex ligation probe amplification (MLPA) assay was set up for large rearrangement analysis. Eleven SLC7A7-specific mutations were identified, seven of them were novel: p.L124P, p.C425R, p.R468X, p.Y274fsX21, c.625 þ 1G4C, DelE4-E11 and DelE6-E11. The novel large deletions originated by the recombination of Alu repeats at introns 3 and 5, respectively, with the same AluY sequence localized at the SLC7A7 3 0 region. The novel MLPA assay is robust and valuable for LPI molecular diagnosis. Our results suggest that genomic rearrangements of SLC7A7 play a more important role in LPI than has been reported, increasing the detection rate from 5.1 to 21.4%. Moreover, the 3 0 region AluY repeat could be a recombination hot spot as it is involved in 38% of all SLC7A7 rearranged chromosomes described so far.

LINE dancing in the human genome: transposable elements and disease

“…The Y-subfamily is young and therefore shows lower than average divergence relative to other genomic Alus, which might explain its high recombination rate. Similar observations implicating a particular 'hotspot' Alu element were reported for multiple cases of rearrangements in the LDL receptor gene causing familial hyper-cholesterolemia [46], and also for the SLC7A7 gene, where one Alu accounted for 38% of all rearranged chromosomes in patients with lysinuric protein intolerance [47]. …”

Molecular and clinical evaluation of Turkish patients with lysinuric protein intolerance

“…To date, a total of 51 different type of mutations in SLC7A7 have been reported in different ethnic groups, including 21 missense, 6 nonsense, 5 splice site, 4 small duplications/insertions, ten small deletions and 5 large genomic rearrangements (Font-Llitjós et al, 2009;Sperandeo et al, 2008). Five different mutations have been previously reported in Turkish patients with LPI, c.14C>T (p.T5I), c.158C>T (p.S53L), and c.253_254delTT in exon 3, c.625 + 1G>A (p.C167G209delinsX) in intron 4, and c.998G>T (p.R333M) in exon 7 (Mykkanen et al, 2000;Sperandeo et al, 2005;Sperandeo et al, 2008).…”

“…In addition, a cluster of LPI patients have been reported in Southern Italy and Japan and sporadic cases have been described worldwide (Font-Llitjós et al, 2009;Norio, 2003;Shoji et al, 2002;Sperandeo et al, 2000). Here, we present clinical, laboratory, and molecular genetic findings of six patients of Turkish origin, with LPI followed for 5-10 years.…”

New mutations in the SLC7A7 gene of two chinese sisters with lysinuric protein intolerance

“…Linkage analysis was used to locate the pathogenic gene of LPI as SLC7A7 mutation which is the solution transport vector. At present, 51 kinds of SLC7A7 gene mutations causing LPI have been found worldwide, including insert (C.1384‐1385 ins ACTA), delete (C.1185‐1188 del TTCT) and point mutations (P.R410X, P.Y457X, P.R 468X, P.L124p, etc) 3, 4. In our cases, there were two heterozygous mutations in the SLC7A7 gene of the two sisters: C.1387 del C and IVS4+1C>T, which has never been reported worldwide.…”