ABCMdb

PMID: 15638824

Castaldo G, Polizzi A, Tomaiuolo R, Cazeneuve C, Girodon E, Santostasi T, Salvatore D, Raia V, Rigillo N, Goossens M, Salvatore F
Comprehensive cystic fibrosis mutation epidemiology and haplotype characterization in a southern Italian population.
Ann Hum Genet. 2005 Jan;69(Pt 1):15-24., [PubMed]

Sentences

No. Mutations Sentence Comment

2 ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Leu1065Pro ABCC7 p.Arg1158* ABCC7 p.Arg1158* ABCC7 p.Leu1077Pro ABCC7 p.Asp579Gly ABCC7 p.Ile502Thr Twelve mutations are peculiar to CF chromosomes from southern Italy: R1158X, 4016insT, L1065P and 711+1G>T are present in 6.3% of CF chromosomes in Campania; G1244E and 852del22 are present in 9.6% of CF chromosomes in Basilicata and 4382delA, 1259insA, I502T, 852del22, 4016insT, D579G, R1158X, L1077P and G1349D are frequent in Puglia (19.6% of CF alleles). Login to comment 3 ABCC7 p.Gly551Asp ABCC7 p.Arg1162* Several mutations frequently found in northern Italy (e.g., R1162X, 711+5G>T) and northern Europe (e.g., G551D, I507del and 621+1G>T) are absent from the studied population. Login to comment 4 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr The I148T-3195del6 complex allele was present in two CF chromosomes, whereas I148T was present in both alleles (as a single mutation) in another CF patient and in five CF carriers; this could result from crossover events. Login to comment 5 ABCC7 p.Arg347Pro ABCC7 p.Glu585* ABCC7 p.Ser549Arg ABCC7 p.Arg1158* ABCC7 p.Leu558Ser The haplotype analysis of three intragenic polymorphisms (IVS8CA, IVS17bTA and IVS17bCA) compared with data from other studies revealed that several mutations (3849+10kbC>T, 1717-1G>A, E585X, 3272-26G>A, L558S, 2184insA and R347P) originated from multiple events, whereas others (R1158X and S549R) could be associated with one or more intragenic recombinant events. Login to comment 14 ABCC7 p.Trp1282* ABCC7 p.Arg1162* ABCC7 p.Tyr122* ABCC7 p.Thr338Ile Most mutations are "private," but some are frequent in specific regions or ethnic groups (Estivill et al. 1997): 2143delT in Germany (Dork et al. 1992), W1282X among Ashkenazim (Shoshani et al. 1992), Y122X in Reunion Island (Chevalier-Porst et al. 1992), 2183AA>G and R1162X in northeast Italy and T338I in Sardinia (Rendine et al. 1997). Login to comment 33 ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Gly1244Glu ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Ile148Thr ABCC7 p.Leu1065Pro ABCC7 p.Arg1158* The 13 mutations in this panel are: F508del, N1303K, G542X, W1282X, 2183AA>G, 1717-1G>A, R553X, I148T, R1158X, 711+1G>T, 4016insT, L1065P and G1244E. Login to comment 49 ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Leu1065Pro ABCC7 p.Arg1158* ABCC7 p.Arg1158* ABCC7 p.Leu1077Pro ABCC7 p.Asp579Gly ABCC7 p.Ile502Thr In particular, 4016insT, R1158X, 711+1 G>T and L1065P had a cumulative frequency of 6.3% in CF chromosomes from Campania; G1244E and 852del22 a cumulative frequency of 9.6% in CF chromosomes from Basilicata; and 4382delA, 1259insA, I502T, 852del22, 4016insT, D579G, R1158X, L1077P and G1349D a cumulative frequency of 19.6% in CF chromosomes from Puglia. Login to comment 52 ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Leu1065Pro ABCC7 p.Arg1158* We also identified three homozygotes for G542X, three for 852del22, two for 2183AA>G, and one each for N1303K, 1717-1G>A, 4016insT, R553X, R1158X and L1065P. Login to comment 55 ABCC7 p.Gly178Arg The DGGE pattern of exon 5 in the CF patient is suggestive of a heterozygous gene variant, which was identified as the G178R missense mutation. Login to comment 62 ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Glu585* ABCC7 p.Ser549Arg ABCC7 p.Gly85Glu ABCC7 p.Leu1065Pro ABCC7 p.Arg1158* ABCC7 p.Ile1005Arg ABCC7 p.Asp1152His ABCC7 p.Leu558Ser ABCC7 p.Leu1077Pro ABCC7 p.Ala349Val ABCC7 p.Gly178Arg ABCC7 p.Asp110His ABCC7 p.Asp579Gly ABCC7 p.Trp1063* ABCC7 p.Ile502Thr ABCC7 p.Arg709Asn ABCC7 p.Tyr849* A procedure for the large-scale analysis of several mutations peculiar to southern Italy is also indicated Mutation Analytical CF alleles Campania Basilicata Puglia Total procedure n = 340 n = 52 n = 350 n = 742 DF508 55.6 55.8 46.8 51.5 N1303K 7.3 3.8 7.7 7.3 G542X 5.0 3.8 7.1 5.9 W1282X 3.5 3.8 0.6 2.2 2183 AA>G 2.3 5.8 0.8 1.9 852del22 0 5.8 3.2 1.9 3% agarose 1717-1G>A 2.3 1.9 1.1 1.8 4382delA 0 0 3.7 1.8 RE (Ear I -) 1259insA 0 0 3.1 1.5 4016insT 2.1 0 1.1 1.5 ASO R553X 1.5 0 1.7 1.5 R1158X 1.5 0 1.3 1.2 ASO or RE (Sfa N 1 -) L1077P 0.6 0 1.9 1.2 I502T 0.3 0 2.0 1.1 RE (Mse I -) 3849+10kbC>T 0 1.9 1.6 0.9 D579G 0 0 1.6 0.8 RE (Avr II +) G1244E 0.9 3.8 0.3 0.8 ASO or RE (Mbo II +) G1349D 0 0 1.7 0.8 RE (Sty I -) 2789+5 G>A 0.6 0 0.8 0.7 711+1 G>T 1.5 0 0 0.7 ASO L1065P 1.2 0 0 0.5 ASO or RE (Mnl I +) R347P 0.3 0 0.9 0.5 2522insC 0.9 0 0 0.4 E585X 0.6 0 0 0.3 G85E 0.6 0 0 0.3 G178R 0.6 0 0 0.3 D1152H 0.3 0 0.3 0.3 I148T-3195del6 0.6 0 0 0.3 I148T (alone) 0 0 0.3 0.1 R334W 0 0 0.3 0.1 DI507 0 0 0.3 0.1 I1005R 0 0 0.3 0.1 3272-26A>G 0.3 0 0 0.1 2711delT 0.3 0 0 0.1 L558S 0 1.9 0 0.1 W1063X 0 0 0.3 0.1 D110H 0.3 0 0 0.1 S549R (A>C) 0 1.9 0 0.1 2184insA 0.3 0 0 0.1 3131del22 0.3 0 0 0.1 R709N 0 0 0.3 0.1 A349V 0 0 0.3 0.1 4015insA 0 0 0.3 0.1 Y849X 0 1.9 0 0.1 Cumulative 91.6 92.1 91.7 91.5 Unknown 8.4 7.9 8.3 8.5 Total 100,0 100,0 100,0 100,0 RE: restriction enzyme (-/+: abolition or introduction of a RE site); ASO: allele specific oligonucleotide Figure 2 Multiplex denaturing gradient gel electrophoretic analysis of exons 8, 5 and 18 of the cystic fibrosis transmembrane regulator gene in a cystic fibrosis patient (case n. Login to comment 64 ABCC7 p.Gly178Arg The analysis revealed an altered pattern of exon 5 in the patient; the sequence analysis identified the G178R mutation at the heterozygous state. Login to comment 71 ABCC7 p.Ile148Thr Finally, two CF patients carried the I148T and 3195del6 mutations in cis, giving rise to a "complex allele." Login to comment 72 ABCC7 p.Ile148Thr Another CF patient from the study, and five CF carriers (data not shown), carried I148T without 3195del6 in cis. Login to comment 73 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr Different haplotypes are linked to I148T alone and to the I148T "complex allele" (see Table 2, group c). Login to comment 81 ABCC7 p.Gly551Asp Several mutations frequent in northern and central Europe, i.e., 621+1G>T, I507del, G551D, were not detected in our population and are also rare in other Mediterranean regions (Rendine et al. 1997; Casals et al. Login to comment 83 ABCC7 p.Arg1162* Our study also revealed differences in the epidemiology of CF mutations between southern and northern Italy: R1162X, frequent (9-14%) in Veneto and Trentino (north-east Italy), is absent in CF patients from southern Italy; 2183AA>G has a frequency of about 10% in north-east Italy versus <2.0% in our region and other Mediterranean populations (Rendine et al. 1997). Login to comment 84 ABCC7 p.Thr338Ile Similarly, 1717-1G>A is more frequent in north-western Italy (5-6%) than in southern Italy (about 2.0% in our population), and T338I, Table 2 Mutations linked to a single haplotype, characteryzed at the level of three CFTR intragenic loci (IVS8CA, IVS17bTA, IVS17bCA) by the indication of the repeats number. Login to comment 85 ABCC7 p.Trp1282* ABCC7 p.Leu1065Pro ABCC7 p.Asp1152His ABCC7 p.Asp110His ABCC7 p.Ile502Thr ABCC7 p.Tyr849* Present study case (n) Mutation references* Haplotype (n. of repeats) Other studies case (n) W1282X 16 17-7-17 26 1, 2, 3 1259insA 11 16-33-13 852del22 11 16-33-13 4016insT 11 16-30-13 I502T 8 16-30-13 L1065P 4 16-30-13 2522insC 4 23-30-13 2789+5G>A 2 17-7-17 9 1, 2, 3 D1152H 2 16-7-13 2711delT 1 16-45-13 2 3 D110H 1 16-32-13 Y849X 1 16-30-13 * References: 1: Morral et al., 1996 2: Claustres et al., 1996 3: Hughes et al., 1996b peculiar to Sardinia, is absent in our population (Rendine et al. 1997). Login to comment 86 ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Leu1065Pro ABCC7 p.Arg1158* ABCC7 p.Leu1077Pro ABCC7 p.Asp579Gly ABCC7 p.Ile502Thr However, 12 mutations (4016insT, R1158X, 711+1G>T, L1065P, G1244E, 4382delA, 1259insA, I502T, 852del22, D579G, L1077P and G1349D) have not been found (or have a low incidence) in populations from the British Isles (Cheadle et al. 1993; Ferec et al. 1992), Spain (Chillon et al. 1994; Casals et al. Login to comment 89 ABCC7 p.Leu1065Pro Other mutations appear to have originated in southern Italy and their frequency has probably been amplified through consanguineous marriages; for instance, 852del22, L1065P and others were identified in homozygosity in several CF patients in whom the haplotypes for the three polymorphisms analyzed were also homozygous. Login to comment 96 ABCC7 p.Gly551Asp For example, the study promoted by the European Concerted Action for Quality Control on CF that involved 136 European laboratories (Dequeker & Cassiman, 1998, 2000) included samples bearing mutations G551D and 621+1G>T, which are virtually absent in southern Europe and Italy (Rendine et al. 1997). Login to comment 97 ABCC7 p.Arg553* ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Arg347Pro ABCC7 p.Gly85Glu ABCC7 p.Leu1077Pro ABCC7 p.Gly178Arg Due to the presence of 'local` mutations, the detection rate with commercial kits for CF chromosomes in Table 3 Mutations linked to different haplotypes possibly due to slippage events, characteryzed at the level of three CFTR intragenic loci (IVS8CA, IVS17bTA, IVS17bCA) by the indication of the repeats number Present study Other studies Cases Haplotype cases (n) (n. of repeats) (n) Haplotype references* (n. of repeats) R347P 4/4 16-32-13 3 16-32-13 1,2,3 1 16-31-13 3 2 17-28-13 1 1 16-45-13 1 L1077P 3/3 17-7-17 1 17-7-17 1 1 17-7-16 1 G85E 2/2 16-24-13 9 16-24-13 2,3 1 16-25-13 2 2183AA>G 14/14 16-31-13 1 16-31-13 3 4 16-30-13 1 R553X 6/11 17-55-13 3 17-58-13 3 3/11 18-55-13 1 17-57-11 1 1/11 16-55-13 2 17-55-13 1,3 1/11 16-55-11 6 17-55-11 1 1 17-52-11 1 1 17-54-11 1 1 17-56-13 3 G1244E 5/6 16-32-13 1 17-34-13 1 1/6 16-34-13 711 +1 G>T 5/5 16-25-13 7 16-25-13 1,2,3 1 16-26-13 1 G1349D 5/6 16-30-13 1/6 16-32-13 G178R 1/2 16-32-13 1 16-30-13 3 1/2 16-32-13 2 16-32-13 1 * References 1: Morral et al. 1996. Login to comment 103 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr Two CF patients from the present study carried the I148T mutation in cis with the 3195del6 mutation; another CF patient, five patients with CBAVD, and five unrelated CF carriers from our population (data not shown), carried I148T not associated in cis with 3195del6. Login to comment 104 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr The chromosomes bearing I148T alone are linked to a different haplotype (of two or three loci) than those linked to the I148T-3195del6 complex allele; a crossover event may be responsible for this. Login to comment 106 ABCC7 p.Ile148Thr It is not clear whether I148T alone is a disease-causing mutation, even though it was described in a CF patient in whom no other CFTR mutation was detected in the whole coding region (Bozon et al. 1994). Login to comment 107 ABCC7 p.Ile148Thr Furthermore, it has been demonstrated that I148T alone alters the transport of HCO3 - across the apical membrane of epithelial cells (Ahn et al. 2001). Login to comment 109 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Glu585* ABCC7 p.Ser549Arg ABCC7 p.Arg1158* ABCC7 p.Leu558Ser Genetists Table 4 Mutations linked to different haplotypes due to recombinant or recurrent events, characteryzed at the level of three CFTR intragenic loci (IVS8CA, IVS17bTA, IVS17bCA) Present study Other studies Cases Haplotype Cases Haplotype (n) (n. of repeats) (n) (n. of repeats) references* I148T and 3195del6 2/2 23-7-17 3 23-7-17 2,3 (in cis) I148T 1/1 23-32-13 S549R (A>C) 1/1 23-33-13 1 16-33-13 2 1717-1G>A 13/13 16-7-17 23 16-7-17 1,2,3 2 16-30-13 1 1 16-32-13 1 R1158X 6/6 16-7-17 1/2 16-7-17 2 1/2 6-45-13 2 1/1 16-31-13 3 1/1 16-45-13 3 3849 +10kbC>T 5/5 23-31-13 2 23-31-13 1 1 16-14-31 4 1 16-7-17 1 3 16-46-13 2 1 16-17-19 2 1 17-31-13 2 E585X 2/2 16-7-17 1 16-32-13 2 1 17-31-13 2 1 16-7-16 see 2 3272-26G>A 1/1 15-7-17 1 16-32-13 1 4 16-7-17 5 L558S 1/1 16-32-13 1 16-32-13 1 1 15-7-17 1 2184 ins A 1/1 16-29-13 1 16-45-13 1 1 16-7-17 1 1 16-24-13 3 * References 1: Morral et al. 1996b. Login to comment 115 ABCC7 p.Gly85Glu ABCC7 p.Leu1077Pro Other mutations (see Table 2, group b) also seem to derive from a founding event, and haplotypes differing by a single microsatellite could depend on slippage phenomena, as already proposed for mutations G85E (Claustres et al. 1996) and L1077P (Morral et al. 1996). Login to comment 116 ABCC7 p.Arg553* In particular, the R553X mutation is associated with a myriad of sequential alleles which are frequently observed on less stable alleles that have more than 50 IVS17b(TA) repeats (Claustres et al. 1996); these could derive from a common ancestor via the slippage phenomena, rather than from recurrent phenomena as suggested by others (Dork et al. 1994). Login to comment 117 ABCC7 p.Arg347Pro A recurrent origin has also been postulated for R347P (Morral et al. 1994; Claustres et al. 1996) since it lies on a triplet with a high mutation rate, and different microsatellite alleles have been associated with this mutation. Login to comment