Homozygous F508 Mutation

[Guest guest]

Hi,

the article below will fuel the ongoing discussion about the genotype-

phenotype connections in pwcf. I am sure that many of us have been

told that being homozygous for dF508 will lead to a worse course of

the disease. But there have always been excemptions from that rule

and here we have something like an explanation.

I will ask at our next clinic visit whether and when it is possible

to find out, whether Fiona is a " cAMP-responder " or not. Given her

good health (touch wood) this could be possible.

Peace

Torsten

Normal Function of the Cystic Fibrosis Conductance Regulator Protein

Can Be Associated with Homozygous F508 Mutation

ISABELLE SERMET-GAUDELUS, BENOIT VALLÉE, ILSE URBIN, TANIA TOROSSI,

RÉMI MARIANOVSKI, ANNE FAJAC, MARIE-NOËLLE FEUILLET, JEAN-LOUIS

BRESSON, GÉRARD LENOIR, JEAN FRANÇOIS BERNAUDIN and ALEKSANDER

EDELMAN

INSERM U 467, Faculté Necker, 156 rue de Vaugirard, 75015 Paris,

France [i.S-G., B.V., T.T., A.E.]; Pediatric Department [i.S-G.,

G.L.], Otorhinolaryngology Department [R.M.], Service de Génétique [M-

N.F.], Centre d'Investigation Clinique [J-L.B.], Hôpital Necker-

Enfants Malades, 149 rue de Sèvres, 75015 Paris, France; Laboratoire

d'Histologie et Biologie Tumorale [i.U., A.F., J.F.B.], Université

Paris 6, Hôpital Tenon, 4 rue de Chine, 75020 Paris, France.

Correspondence: Aleksander Edelman, INSERM U 467, Faculté Necker, 156

rue de Vaugirard, 75015 Paris, France; e-mail:edelman@...

Cystic fibrosis (CF) is caused by mutations of the gene encoding for

the CFTR (CF transmembrane conductance regulator) protein. The most

frequent mutation, the F508 mutation, results in a defective cAMP-

regulated chloride transport in the epithelial cells. The spectrum of

clinical manifestations in patients bearing homozygous F508 mutations

can vary considerably, suggesting that, in the patients with a mild

disease, CFTR could be partly functional. To test this hypothesis, we

explored in nasal ciliated epithelial cells (NCC) of 9 control

subjects and 23 F508 homozygous patients the anion conductive pathway

by a halide sensitive fluorescent dye assay SPQ (6-methoxy-N-3'-

sulfopropylquinolinium) and the CFTR transcript levels by RT-PCR. As

50% represented the lowest fraction of the control subjects NCC

demonstrating a cAMP-dependent conductance, a CF patient was

considered as " cAMP responder " if at least 50% of the NCC tested

displayed a cAMP-dependent conductive pathway. According to these

criteria, 8 of the 23 patients were considered as cAMP responders.

They had a significantly less severe disease considering the

respiratory function and infectious status. The amount of CFTR mRNA

did not differ between the control subjects and the patients. No

statistical correlation could be found between the transcript level

and the expression of a cAMP conductive pathway. This cAMP-dependent

Cl- conductance detected in homozygous NCC could be due to a residual

CFTR activity and may explain the mild phenotypes observed in some

F508 homozygous patients.

Abbreviations:

CFTR, cystic fibrosis transmembrane conductance regulator

CF, cystic fibrosis

cAMP, cyclic AMP

FEV1, forced expiratory volume

FVC, forced vital capacity

SPQ, 6-methoxy-N-3'-sulfopropylquinolinium