ABCMdb

PMID: 25583415

Terlizzi V, Carnovale V, Castaldo G, Castellani C, Cirilli N, Colombo C, Corti F, Cresta F, D'Adda A, Lucarelli M, Lucidi V, Macchiaroli A, Madarena E, Padoan R, Quattrucci S, Salvatore D, Zarrilli F, Raia V
Clinical expression of patients with the D1152H CFTR mutation.
J Cyst Fibros. 2015 Jul;14(4):447-52. doi: 10.1016/j.jcf.2014.12.012. Epub 2015 Jan 10., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC7 p.Asp1152His Original Article Clinical expression of patients with the D1152H CFTR mutation Vito Terlizzi a , Vincenzo Carnovale b , Giuseppe Castaldo c,d , Carlo Castellani e , Natalia Cirilli f , Carla Colombo g , Fabiola Corti g , Federico Cresta h , Alice D'Adda g , Marco Lucarelli i , Vincenzina Lucidi j , Annamaria Macchiaroli k , Elisa Madarena l , Rita Padoan m , Serena Quattrucci n , Donatello Salvatore o , Federica Zarrilli p , Valeria Raia a,Ìe; a Dipartimento di Scienze Mediche Traslazionali, Sezione di Pediatria, Universit&#e0; di Napoli Federico II, Naples, Italy b Centro Fibrosi Cistica Adulti, Dipartimento di Scienze Traslazionali, Universit&#e0; di Napoli Federico II, Naples, Italy c CEINGE-Biotecnologie avanzate, Naples, Italy d Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit&#e0; di Napoli Federico II, Naples, Italy e Centro Fibrosi Cistica, Azienda Ospedaliera Universitaria Integrata, Verona, Italy f Centro Regionale Fibrosi Cistica, Dipartimento Materno-Infantile, Ospedali Riuniti Ancona, Ancona, Italy g Centro Fibrosi Cistica, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy h Centro Fibrosi Cistica, Dipartimento di Pediatria, IRCCS G. Gaslini, Genova, Italy i Dipartimento di Biotecnologie Cellulari ed Ematologia, Istituto Pasteur Fondazione Cenci Bolognetti, Sapienza Universit&#e0; e Policlinico Umberto I, Rome, Italy j Unit&#e0; di Fibrosi Cistica, IRCCS Ospedale Pediatrico Bambin Ges&#f9;, Rome, Italy k Centro Regionale Fibrosi Cistica, Ospedale Cardarelli, Campobasso, Italy l Centro Fibrosi Cistica, Ospedale Giovanni Paolo II, Lamezia, Italy m Centro di supporto Fibrosi Cistica, Dipartimento di Pediatria, Universit&#e0; di Brescia, Brescia, Italy n Dipartimento di Pediatria, Centro Fibrosi Cistica, Sapienza Universit&#e0; e Policlinico Umberto I, Rome, Italy o Centro Fibrosi Cistica, Centro Pediatrico Bambino Ges&#f9; Basilicata, AOR San Carlo, Potenza, Italy p Dipartimento di Bioscienze e Territorio, Universit&#e0; del Molise, Isernia, Italy Received 4 September 2014; revised 17 December 2014; accepted 18 December 2014 Available online 10 January 2015 Abstract Background: Discordant results were reported on the clinical expression of subjects bearing the D1152H CFTR mutation, and also for the small number of cases reported so far. Login to comment 1 ABCC7 p.Asp1152His Methods: A retrospective review of clinical, genetic and biochemical data was performed from individuals homozygous or compound heterozygous for the D1152H mutation followed in 12 Italian cystic fibrosis (CF) centers. Login to comment 2 ABCC7 p.Asp1152His Results: 89 subjects carrying at least D1152H on one allele were identified. Login to comment 4 ABCC7 p.Asp1152His Over half of the 74 subjects compound heterozygous for D1152H and a I-II-III class mutation had borderline or pathological sweat test and respiratory or gastrointestinal symptoms; one third had pulmonary bacteria colonization and 10/74 cases had complications (i.e. diabetes, allergic bronchopulmonary Abbreviations: CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; PI, pancreatic insufficiency; PS, pancreatic sufficiency; CFTR-RD, CFTR related disorders; CBAVD, congenital bilateral absence of vas deferens; SC, sweat chloride; W, weight; pc, percentile; H, height; BMI, body mass index; FEV1, forced expiratory volume in 1 s; PA, Pseudomonas aeruginosa; BC, Burkholderia cepacia; SM, Stenotrophomonas malthophilia; SA, Staphylococcus aureus; MRSA, methicillin resistant Staphylococcus aureus; CFRD, cystic fibrosis related diabetes; CFLD, CF-associated liver disease; ABPA, allergic bronchopulmonary aspergillosis; MI, meconium ileus; DIOS, distal intestine obstruction syndrome; NBS, newborn screening. Login to comment 12 ABCC7 p.Asp1152His Finally, 8 subjects compound heterozygous for D1152H and a IV-V class mutation showed very mild disease. Login to comment 13 ABCC7 p.Asp1152His Conclusions: The natural history of subjects bearing the D1152H mutation is widely heterogeneous and is influenced by the mutation in trans. Login to comment 15 ABCC7 p.Asp1152His Keywords: Cystic fibrosis; D1152H; Neonatal screening; Genotype/phenotype 1. Login to comment 23 ABCC7 p.Asp1152His ABCC7 p.Asp1152His The D1152H mutation (p.Asp1152His) is a class IV mutation causing the production of an abnormal CFTR protein that is only partially activated by cAMP, consequently it is associated to some CFTR protein residual activity [11]. Login to comment 24 ABCC7 p.Asp1152His Initially, D1152H was associated to a congenital bilateral absence of vas deferens (CBAVD) or to CF with late onset pulmonary disease and borderline or normal sweat chloride values [12,13]. Login to comment 27 ABCC7 p.Asp1152His In 2011 a higher frequency of the D1152H mutation was detected in individuals referred for symptoms suggestive of CF compared with healthy individuals included in a CF carrier screening program [15]. Login to comment 28 ABCC7 p.Asp1152His Recently, the D1152H mutation was included in a list of nine CFTR mutations associated to a higher risk of pancreatitis but not of CF [16]. Login to comment 29 ABCC7 p.Asp1152His ABCC7 p.Asp1152His Finally, the CFTR2 database considered D1152H as a mutation with variable penetrance, i.e., the D1152H in trans with a CF-causing mutation may or may not cause CF (http://www.http. com//www.cftr2). Login to comment 30 ABCC7 p.Asp1152His Thus, the data so far available about phenotypes associated to D1152H were obtained in small numbers of subjects. Login to comment 31 ABCC7 p.Asp1152His So the primary aim of our study is to describe the clinical course of a large cohort of patients bearing the D1152H mutation in trans with different class mutations. Login to comment 34 ABCC7 p.Asp1152His A descriptive study was designed to include patients either homozygous or compound-heterozygous for the D1152H CFTR mutation (89 cases). Login to comment 53 ABCC7 p.Asp1152His Results 89 subjects carrying at least one D1152H mutation were identified (Table 1): 7 were homozygous (median age: 20 years, range: 4-47 years) and 82 were compound heterozygous for other mutations (median age: 15 years, range: 1-68 years). Login to comment 54 ABCC7 p.Asp1152His ABCC7 p.Asp1152His Among the latter, 74/82 (median age 13 years, range: 1-68 years) patients were compound heterozygous for D1152H and a class I-II-III mutation, while 8/82 (median age 10 years, range: 2-47 years) patients were compound heterozygous for D1152H and a class IV-V mutation. Login to comment 55 ABCC7 p.Asp1152His Linkage analysis using 7 intragenic short tandem repeats [30] performed on 49/89 patients excluded the recurrent origin of the D1152H mutation. Login to comment 57 ABCC7 p.Asp1152His ABCC7 p.Asp1152His Homozygous patients for D1152H b10 years 2/7 patients homozygous for the D1152H mutation were 10 years old or less (4 and 5 years old, respectively). Login to comment 61 ABCC7 p.Asp1152His ABCC7 p.Asp1152His Homozygous patients for D1152H N10 years 5/7 patients homozygous for the D1152H mutation were N10 years old (median age: 36 years; range: 13 to 47 years old). Login to comment 67 ABCC7 p.Asp1152His Compound heterozygous patients with a class I-II-III mutation b10 years 25/74 patients compound heterozygous for D1152H and a class I-II-III mutation were 10 years old or less (median age: 5 years; range: 1-9 years). Login to comment 75 ABCC7 p.Asp1152His Compound heterozygous patients with a class I-II-III mutation N10 years 49/74 patients compound heterozygous for D1152H and a class I-II-III mutation were N10 years old (median age: 35 years; range: 12-68 years). Login to comment 82 ABCC7 p.Asp1152His Compound heterozygous patients with a class IV-V mutation b10 years 4/8 patients compound heterozygous for D1152H and a class IV-V mutation had 10 years or less (median age: 4.5 years; range: 2-8 years). Login to comment 84 ABCC7 p.Asp1152His Only 1 patient had SC in the Table 1 Genetic analysis of 91 patients with D1152H mutation. Login to comment 85 ABCC7 p.Trp1282* ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg74Trp ABCC7 p.Leu1065Pro ABCC7 p.Leu1065Pro ABCC7 p.Arg1158* ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp579Gly ABCC7 p.Asp579Gly ABCC7 p.Tyr849* Legacy name Protein name CDNA name Patients Homozygous for the D1152Ha D1152H p.Asp1152His c.3454GNC 7 Compound heterozygous for class I-II-III mutationsa : 74 F508del p.Phe508del c.1521_1523delCTT 43 G542X p.Gly542X c.1624GNT 7 N1303K p.Asn1303Lys c.3909CNG 4 1717-1GNA No protein name c.1585-1GNA 4 R1158X p.Arg1158X c.3472CNT 4 2183AANG p.Lys684SerfsX38 c.2051_2052delAAinsG 2 W1282X p.Trp1282X c.3846GNA 2 711 + 1GNT No protein name c.579 + 1GNT 1 Y849X p.Tyr849X c.2547CNA 1 L1065P p.Leu1065Pro c.3194 TNC 1 4016insT p.Ser1297PhefsX5 c.3884_3885insT 1 R1066H p.Arg1066His c.3197GNA 2 R1066C p.Arg1066Cys c.3196CNT 1 4382delA p.Glu1418ArgfsX14 c.4251delA 1 Compound heterozygous for class IV-V mutationsa : 8 (TG)12T5 No protein name Not available 2 2789 + 5GNA No protein name c.2657 + 5GNA 1 D579G p.Asp579Gly c.1736ANG 1 [R74W;V201M; D1270N] No protein name Not available 1 3849 + 10KbCNT No protein name c.3717 + 12191CNT 1 R347H p.Arg347His c.1040GNA 1 R347P p.Arg347Pro c.1040GNC 1 a Protein name and cDNA name from the CFTR2 database (http://www.http. com//www.cftr2) and http://www.genet.sickkids.on.ca/Home.html. Login to comment 88 ABCC7 p.Asp1152His Compound heterozygous patients with a class IV-V mutation N10 years 4 patients compound heterozygous for D1152H and a class IV-V mutation were N10 years old (median age: 15.5 years; range: 12-47 years). Login to comment 94 ABCC7 p.Asp1152His Homozygous patients for F508del N10 years As shown in Table 2, 48 CF patients homozygous for the F508del mutation and N10 years old (median age: 24 years; range: 11-58 years) were evaluated to compare their clinical expression with the 49 patients N10 years compound heterozygous for D1152H and a class I-II-III mutation. Login to comment 96 ABCC7 p.Asp1152His As shown in Table 2, the occurrence of several symptoms or complications i.e., pathological sweat test (p b 0.001), meconium ileus (p b 0.01), pancreatic insufficiency (p b 0.0001), diabetes (p b 0.001), nasal polyposis (p b 0.01), respiratory insufficiency as evaluated by the number of cases with an altered FEV1 (p b 0.05), bacterial colonization by P. aeruginosa (p b 0.001), S. aureus (p b 0.05) and S. maltophilia (p b 0.01), bronchiectasis (p b 0.05) and atelectasis (p b 0.05) was significantly more frequent in the 48 patients homozygous for the F508del mutation as compared to the 49 patients compound heterozygous for D1152H and a class I-IIIII mutation. Login to comment 98 ABCC7 p.Asp1152His Discussion Our data indicate that the clinical expression of CF in patients with the D1152H mutation is heterogeneous, and may in part depend on the mutation in trans. Login to comment 99 ABCC7 p.Asp1152His As a matter of fact, homozygous patients for the D1152H mutation show a very mild clinical course, with normal SC in all but one case, PS, lung function test in the normal range for age and gender, good nutritional status and no airway bacteria colonization or other complications. Login to comment 101 ABCC7 p.Asp1152His In particular Peleg et al. [15] reported a series of 4 homozygous patients for D1152H: all had PS, but two cases had recurrent pneumonia since infancy or bronchiectasis with recurrent lung infections. Login to comment 103 ABCC7 p.Asp1152His Furthermore, the only patient homozygous for the D1152H mutation described by Burgel had recurrent bronchitis and a multiple pulmonary colonization [11]. Login to comment 105 ABCC7 p.Asp1152His Among individuals carrying D1152H and a class I-II-III mutation, 19/71 (26.7%) cases showed SC over 60 mmol/L and suggestive clinical symptoms: these patients were diagnosed as having CF. Login to comment 106 ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His In the same group 20/71 (28%) cases had a borderline SC and suggestive symptoms of CF: these patients were classified Table 2 Clinical characteristics of patients in the different groups: A) homozygous patients for the D1152H mutation b10 years; B) homozygous patients for the D1152H mutation N10 years; C) compound heterozygous for D1152H and a class I-II-III mutation b10 years; D) compound heterozygous for D1152H and a class I-II-III mutation N10 years; E) compound heterozygous for D1152H and a class IV-V mutation b10 years; F) compound heterozygous for D1152H and a class IV-V mutation N10 years; G) homozygous patients for the F508del mutation N10 years. Login to comment 110 ABCC7 p.Asp1152His These results agree with the data reported previously by Burgel [11] but are in disagreement with the study by LaRusch et al. [16] that reported the D1152H was carried in patients with pancreatitis but not with CF. Login to comment 116 ABCC7 p.Asp1152His When we analyzed data in the group of patients b10 years old (23/71 patients) we found that these patients also had a more severe phenotype than D1152H homozygous patients (i.e., 2 cases with borderline SC, 1 with MI, 2 cases with PI). Login to comment 117 ABCC7 p.Asp1152His ABCC7 p.Asp1152His It must be noted that the age at diagnosis for patients diagnosed for symptoms from this subgroup is higher than that of patients homozygous for the D1152H mutation and that of patients compound heterozygous for D1152H and a class IV-V mutation. Login to comment 119 ABCC7 p.Asp1152His In any case, even if a number of patients compound heterozygous for D1152H and a mutation of class I-II-III show symptoms and complications typically found in CF patients, clinical expression of CF is milder and the occurrence of complications more rare as compared to CF patients homozygous for the F508del mutation, despite that the 48 patients of the latter group examined in our study are meanly younger. Login to comment 122 ABCC7 p.Asp1152His On the contrary, even if there is a significant difference in the frequency, pulmonary colonizations and bronchiectasis are observed in both groups, and this suggests that patients compound heterozygous for D1152H and a class I-III mutation must be carefully monitored at the pulmonary level. Login to comment 123 ABCC7 p.Asp1152His Individuals compound heterozygous for D1152H and a class IV-V mutation show a very mild clinical course. Login to comment 128 ABCC7 p.Asp1152His Most of them carry a rare mutation in trans with the D1152H mutation and the question on how deep should be the molecular analysis in patients with normal SC is still unanswered [31]. Login to comment 129 ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His In conclusion, clinical outcomes in individuals carrying D1152H and a class I-II-III mutation seem to be more severe than in those with D1152H and a class IV-V mutation and in D1152H homozygotes (most of this group do not meet CF diagnostic criteria). Login to comment 130 ABCC7 p.Asp1152His The former group could possibly benefit from early diagnosis, suggesting that the D1152H mutation should be included in panels for molecular analysis. Login to comment 131 ABCC7 p.Asp1152His Actually the extent to which D1152H has variable penetrance to cause disease is unknown. Login to comment