title: Complex allele [-102T>A+S549R(T>G)] is associated with milder forms of cystic fibrosis than allele S549R(T>G) alone.
abstract: We recently reported a novel complex allele in the cystic fibrosis transmembrane regulator (CFTR) gene, combining a sequence change in the minimal CFTR promoter (-102T>A) and a missense mutation in exon 11 [S549R(T>G)]. Here we compare the main clinical features of six patients with cystic fibrosis (CF) carrying the complex allele [-102T>A+S549R(T>G)] with those of 16 CF patients homozygous for mutation S549R(T>G) alone. Age at diagnosis was higher, and current age was significantly higher (P=0.0032) in the group with the complex allele, compared with the S549R/S549R group. Although the proportion of patients with lung colonization was similar in both groups, the age at onset was significantly higher in the group with the complex allele (P=0.0022). Patients with the complex allele also had significantly lower sweat test chloride values (P=0.0028) and better overall clinical scores (P=0.004). None of the 22 patients reported in this study had meconium ileus. All 16 patients homozygous for S549R(T>G), however, were pancreatic insufficient, as compared with 50% of patients carrying the complex allele (P=0.013). Moreover, the unique patient homozygous for [-102T>A+S549R(T>G)] presented with a mild disease at 34 years of age. These observations strongly suggest that the sequence change (-102T>A) in the CFTR minimal promoter could attenuate the severe clinical phenotype associated with mutation S549R(T>G).
authors.affiliation: Laboratoire de Génétique Moléculaire, Institut de Biologie, CHU, CNRS IGH UPR 1142, Montpellier, France.
authors.forename: M C
authors.initials: MC
authors.lastname: Romey
authors.forename: C
authors.initials: C
authors.lastname: Guittard
authors.forename: J P
authors.initials: JP
authors.lastname: Chazalette
authors.forename: P
authors.initials: P
authors.lastname: Frossard
authors.forename: K P
authors.initials: KP
authors.lastname: Dawson
authors.forename: M A
authors.initials: MA
authors.lastname: Patton
authors.forename: T
authors.initials: T
authors.lastname: Casals
authors.forename: T
authors.initials: T
authors.lastname: Bazarbachi
authors.forename: E
authors.initials: E
authors.lastname: Girodon
authors.forename: G
authors.initials: G
authors.lastname: Rault
authors.forename: D
authors.initials: D
authors.lastname: Bozon
authors.forename: F
authors.initials: F
authors.lastname: Seguret
authors.forename: J
authors.initials: J
authors.lastname: Demaille
authors.forename: M
authors.initials: M
authors.lastname: Claustres
mesh_terms: D000483:Alleles; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010641:Phenotype; D017354:Point Mutation; D011379:Prognosis; D017422:Sequence Analysis, DNA
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator