ABCMdb

PMID: 20691141

Tomaiuolo AC, Alghisi F, Petrocchi S, Surace C, Roberti MC, Bella S, Lucidi V, Angioni A
Clinical hallmarks and genetic polymorphisms in the CFTR gene contribute to the disclosure of the A1006E mutation.
Clin Invest Med. 2010 Aug 1;33(4):E234-9., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC7 p.Ala1006Glu Clinical hallmarks and genetic polymorphisms in the CFTR gene contribute to the disclosure of the A1006E mutation Anna Cristina Tomaiuolo MSc1 Federico Alghisi MD2 Stefano Petrocchi MSc1 Cecilia Surace PhD1 Maria Cristina Roberti PhD1 Sergio Bella MD2 Vincenzina Lucidi MD2 Adriano Angioni MD1 1 Cytogenetics and Molecular Genetics Laboratory. Login to comment 6 ABCC7 p.Ala1006Glu From a familial study of a patient with CBAVD, carrier of the A1006E mutation, we have observed its strict association with the polymorphism 5T-TG11. Login to comment 7 ABCC7 p.Ala1006Glu In order to speed up the genetic diagnosis and to correlate the clinical setting to this genetic feature, we have directly investigated the exon 17a, where the A1006E mutation is located, of five cystic fibrosis patients belonging to two unrelated families. Login to comment 9 ABCC7 p.Gln220* ABCC7 p.Ala1006Glu One more family with two affected individuals carrying the Q220X/A1006E mutations was investigated for the poly-T polymorphism. Login to comment 10 ABCC7 p.Ala1006Glu All the members were found to have the A1006E mutation and the 5T-TG11 in the same DNA strand, demonstrating that this strategy is a reliable and inexpensive method for genotyping the CFTR gene. Login to comment 14 ABCC7 p.Ile148Thr Moreover, molecular diagnosis of CF, particularly for non-classical CF or CFTR-related diseases, involves rare mutations and requires extensive gene sequencing, a time consuming and costly approach.2 In order to overcome this problem, many attempts have been ORIGINAL RESEARCH made to use linkage analysis of polymorphic loci to known mutations because intragenic marker haplotype analysis has been shown to facilitate mutation screening.3 In fact, it is well known that F508del mutation is in linkage disequilibrium with the polymorphic tract 9T4 and the I148T sequence variation is frequently associated with the 3199del6 mutation.5,6 The poly T tract, a string of thymidine bases located in intron 8 of the CFTR gene, may be associated with non-classical CF or CFTR-related disorders depending on its size.7 The 5T variant decreases the efficiency of intron 8 splicing when the associated TG sequence is 12 or 13 repeats in length, while 11 repeats seems to be irrelevant.8,9 5T-TG analysis is routinely performed in our lab and we have investigated many patients, including some cases of Congenital Bilateral Absence of Vas Deferent (CBAVD). Login to comment 15 ABCC7 p.Ala1006Glu Among these, due to familial segregation studies, we have found that the A1006E mutation is in cis with the 5T-TG11 polymorphism. Login to comment 16 ABCC7 p.Ala1006Glu Based on these observations we have decided to use the 5T-TG11 haplotype to trace the A1006E mutation in five CF patients with incomplete genotyping, belonging to two unrelated families. Login to comment 17 ABCC7 p.Ala1006Glu Two additional related patients, both compound heterozygotes carrying the A1006E, were investigated for the Tn-TGm locus to implement the finding of this association. Login to comment 28 ABCC7 p.Gln220* ABCC7 p.Ala1006Glu They also carried the same CFTR gene mutations (Q220X/A1006E). Login to comment 56 ABCC7 p.Ala1006Glu Family 1 and Family 3 members underwent exon 17a sequencing that revealed the 3149 C>A mutation (A1006E) in all of them. Login to comment 57 ABCC7 p.Val562Ile Exon 10 was also analyzed in order to complete the haplotype feature: M470 was homozygous in each individual while the V562I sequence variation was present in all but one patient. Login to comment 58 ABCC7 p.Ala1006Glu A familial study involving all the informative relatives was then carried out showing the linkage of 5T-TG11 with the A1006E mutation. Login to comment 59 ABCC7 p.Ala1006Glu Discussion The A1006E is included in the group of the so called "borderline mutations".7 It is a missense defect due to the C to A nucleotide variation at 3149, within the exon 17a, resulting in the amino acid change alanine to glutamic acid. Login to comment 60 ABCC7 p.Ala1006Glu The involved proteic region is the second membrane spanning domain that contributes to complete the proper CFTR channel structure In our CF patient`s database the A1006E mutation has been detected, using the trace of the 5T-TG11 polymorphism, in 3 out of 436 CF chromosomes, accounting for an estimated incidence of about 0.7%. Login to comment 61 ABCC7 p.Val562Ile A similar rate has been observed in the Spanish population, while, surprisingly, this mutation was not detected among the Hispanics of the Latin American populations.11 The same study identified its association with the V562I and the IVS8-5T in a complex allele that is now updated including the TG11 polymorphism reported from our investigations. Login to comment 62 ABCC7 p.Ala1006Glu These results have been further confirmed through familial studies of informative relatives that showed the same linkage of the 5T-TG11 polymorphism with the A1006E mutation. Login to comment 64 ABCC7 p.Arg117His Some haplotypes contain loci mutually influencing the gene function, such as the R117H-poly-T association;12-14 others are neutral or ameliorative. Login to comment 66 ABCC7 p.Ala1006Glu Among the A1006E partners a possible role in modifying gene activity may be attributed to the poly-5T-TG tract, and indirectly, to M470V. Login to comment 68 ABCC7 p.Val562Ile Moreover, all but one case (Pt1) show the V562I revealing a weaker association between this sequence variation and the previously described haplotype. Login to comment 69 ABCC7 p.Ala1006Glu The A1006E mutation has been detected in large series of patients with CBAVD or CF but scarce information is available from the clinical setting. Login to comment 72 ABCC7 p.Ala1006Glu Despite the late onset of clinical presentation (mean age at di- Tomaiuolo et al. A1006E mutation and TG(m)Tn polymorphism (c) 2010 CIM Clin Invest Med • Vol 33, no 4, August 2010 E237. Login to comment 73 ABCC7 p.Gln220* ABCC7 p.Ala1006Glu ABCC7 p.Ala1006Glu ABCC7 p.Ala1006Glu ABCC7 p.Val562Ile ABCC7 p.Val562Ile TABLE 1. Allelic genotyping of the patients with CFTR geneTABLE 1. Allelic genotyping of the patients with CFTR geneTABLE 1. Allelic genotyping of the patients with CFTR geneTABLE 1. Allelic genotyping of the patients with CFTR geneTABLE 1. Allelic genotyping of the patients with CFTR geneTABLE 1. Allelic genotyping of the patients with CFTR gene Patients Haplotype Mutations Tn-TGm Sequence variations Sequence variations Pt1 Strand 1 F508del 9T-TG10 M470V Strand 2 A1006E 5T-TG11 M470V - Pts2-3 Strand 1 Q220X 7T-TG11 M470V Strand 2 A1006E 5T-TG11 M470V V562I Pts4-7 Strand 1 F508del 9T-TG10 M470V Strand 2 A1006E 5T-TG11 M470V V562I TABLE 2. Phenotypic features of patients with CFTR geneTABLE 2. Phenotypic features of patients with CFTR geneTABLE 2. Phenotypic features of patients with CFTR geneTABLE 2. Phenotypic features of patients with CFTR geneTABLE 2. Phenotypic features of patients with CFTR geneTABLE 2. Phenotypic features of patients with CFTR geneTABLE 2. Phenotypic features of patients with CFTR geneTABLE 2. Phenotypic features of patients with CFTR gene Pts Age at diagnosis Sweat test Current clinical statusCurrent clinical statusCurrent clinical statusCurrent clinical statusCurrent clinical status (years) (mmol/L) Age (years) X-Ray Lung Assessment FEV1% PS ARP 1 35 Cl: 84 36 Bronchiectasis 61 - - 2 21 Cl: 74 36 Bronchiectasis 76 - + 3 14 Cl: 76 29 Bronchiectasis 73 + - 4 IRT + Na: 76 18 Bronchial thickening 110 + - 5 16 Na: 121 34 Initial bronchiectasis 86 + - 6 14 Na: 119 32 Bronchiectasis; lobe excision 74 - + 7 13 Na: 97 31 Bronchial thickening 91 + - IRT: Immunoreactive Trypsinogen Test FEV1: Forced Expiratory Volume in 1 second PS: Pancreatic Sufficiency ARP: Acute Recurrent Pancreatitis ` IRT: Immunoreactive Trypsinogen Test FEV1: Forced Expiratory Volume in 1 second PS: Pancreatic Sufficiency ARP: Acute Recurrent Pancreatitis ` IRT: Immunoreactive Trypsinogen Test FEV1: Forced Expiratory Volume in 1 second PS: Pancreatic Sufficiency ARP: Acute Recurrent Pancreatitis ` IRT: Immunoreactive Trypsinogen Test FEV1: Forced Expiratory Volume in 1 second PS: Pancreatic Sufficiency ARP: Acute Recurrent Pancreatitis ` IRT: Immunoreactive Trypsinogen Test FEV1: Forced Expiratory Volume in 1 second PS: Pancreatic Sufficiency ARP: Acute Recurrent Pancreatitis ` IRT: Immunoreactive Trypsinogen Test FEV1: Forced Expiratory Volume in 1 second PS: Pancreatic Sufficiency ARP: Acute Recurrent Pancreatitis ` IRT: Immunoreactive Trypsinogen Test FEV1: Forced Expiratory Volume in 1 second PS: Pancreatic Sufficiency ARP: Acute Recurrent Pancreatitis ` IRT: Immunoreactive Trypsinogen Test FEV1: Forced Expiratory Volume in 1 second PS: Pancreatic Sufficiency ARP: Acute Recurrent Pancreatitis ` agnosis of 16.2 ± 10.5 years, median age of 14 years) the course of the disease leads to a complete phenotypic expression. Login to comment 81 ABCC7 p.Ala1006Glu An interesting observation is the unexpectedly elevated incidence of the A1006E mutation within our data base of CF patients. Login to comment 83 ABCC7 p.Ala1006Glu Moreover, the geographic origin of our families may suggest a possible relationship for the high rate of the A1006E, with the historical Spanish domination along the south-western regions of our country. Login to comment 84 ABCC7 p.Ala1006Glu In conclusion, the study reports a detailed description of the phenotypic spectrum of the A1006E mutation, providing useful information for a ready and inexpensive genotyping in selected cases. Login to comment 86 ABCC7 p.Ala1006Glu For the clinical setting, these results illustrate the importance of an early detection of the disease - before the patients become symptomatic;17 IRT and sweat test appear to be sensitive diagnostic tests for patients affected by the A1006E mutation. Login to comment