ABCMdb

PMID: 17681820

Masson E, Le Marechal C, Levy P, Chuzhanova N, Ruszniewski P, Cooper DN, Chen JM, Ferec C
Co-inheritance of a novel deletion of the entire SPINK1 gene with a CFTR missense mutation (L997F) in a family with chronic pancreatitis.
Mol Genet Metab. 2007 Sep-Oct;92(1-2):168-75. Epub 2007 Jul 27., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC7 p.Leu997Phe Co-inheritance of a novel deletion of the entire SPINK1 gene with a CFTR missense mutation (L997F) in a family with chronic pancreatitis Emmanuelle Masson a,b , Ce &#b4;dric Le Mare &#b4;chal a,b,c,d , Philippe Levy e , Nadia Chuzhanova f , Philippe Ruszniewski e , David N. Cooper g , Jian-Min Chen a,c,*, Claude Fe &#b4;rec a,b,c,d a INSERM, U613, 29220 Brest, France b Faculte &#b4; de Me &#b4;decine de Brest et des Sciences de la Sante &#b4;, Universite &#b4; de Bretagne Occidentale, 29238 Brest, France c Etablissement Franc &#b8;ais du Sang-Bretagne, 29220 Brest, France d Laboratoire de Ge &#b4;ne &#b4;tique Mole &#b4;culaire et d`Histocompatibilite &#b4;, Centre Hospitalier Universitaire de Brest, Ho c6;pital Morvan, 29220 Brest, France e Po c6;le des Maladies de l`Appareil Digestif, Service de Gastroente &#b4;rologie-Pancre &#b4;atologie, Assistance Publique-Hopitaux de Paris, Ho c6;pital Beaujon, Clichy, France f Department of Biological Sciences, University of Central Lancashire, Preston PR1 2HE, UK g Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK Received 24 May 2007; received in revised form 13 June 2007; accepted 13 June 2007 Available online 27 July 2007 Abstract Quantitative fluorescent multiplex PCR (QFM-PCR) was established in order to make possible the rapid and efficient mutational analysis of the pancreatic secretory trypsin inhibitor (SPINK1) gene. Login to comment 5 ABCC7 p.Leu997Phe Remarkably, in all three affected individuals, the SPINK1 deletion was found to be co-inherited with a heterozygous p.L997F missense mutation in the unlinked CFTR gene, a lesion previously reported to be associated with a variety of cystic fibrosis-related diseases including idiopathic pancreatitis. Login to comment 25 ABCC7 p.Leu997Phe Interestingly, this deletion was found to be co-inherited with a p.L997F missense mutation in the CFTR gene [MIM #602421]. Login to comment 92 ABCC7 p.Leu997Phe The SPINK1 gene deletion co-inherits with a CFTR p.L997F missense mutation The co-inheritance of SPINK1 and CFTR variants/ mutations has been frequently identified in patients with chronic pancreatitis or recurrent acute pancreatitis (e.g., Fig. 2. Login to comment 108 ABCC7 p.Leu997Phe In this study, a previously reported missense mutation in the CFTR gene (p.L997F [37]) was found to be present in heterozygous form in all three patients carrying the SPINK1 gene deletion in the family in question (Fig. 5) [only the three patients were available for analysis]. Login to comment 109 ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe Although homozygosity for p.L997F appears not to have given rise to clinical symptoms in a child [38], heterozygosity for p.L997F has been reported in association with a variety of different conditions that have collectively been described as cystic fibrosis-related diseases (including sporadic idiopathic pancreatitis [39-42], disseminated bronchiectasis [43], primary sclerosing cholangitis [44] and Fig. 5. Login to comment 112 ABCC7 p.Leu997Phe The genotypes (p.L997F in the CFTR gene co-inherited with the SPINK1 gene deletion) are shown below the subjects available for genetic analysis. Login to comment 129 ABCC7 p.Leu997Phe We therefore surmise that whilst mutation of p.L997F may be insufficient on its own to cause disease, it may well act synergistically with other genetic factors to confer increased risk of cystic fibrosis-related disease. Login to comment 130 ABCC7 p.Leu997Phe Nevertheless, given that the deletion of the entire SPINK1 gene is clearly disease-causing in its own right, the CFTR p.L997F missense mutation (which has a frequency of <1% in the French population [41,47]) may have simply acted as a disease modifier, at least in the context of this particular family. Login to comment