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Detection of a cystic fibrosis modifier locus for meconium ileus on human chromosome 19q13

Nature Genetics volume 22, pages 128–129 (1999)Cite this article

Cystic fibrosis (CF) is a simple, autosomal recessive disorder caused by mutations in CFTR, encoding the CF transmembrane conductance regulator1,2. The molecular defects resulting from over 800 different mutations in CFTR only partially explain the clinical heterogeneity of the disease. While most CF patients suffer from pancreatic enzyme insufficiency, 10–15% of patients have a pancreatic-sufficient phenotype, which has been correlated with a group of mild CFTR mutations3 characterized by their ability to confer residual chloride-channel function. Meconium ileus (MI) is a severe intestinal obstruction detected in a subset (15-20%) of CF patients at birth. Although MI usually occurs in patients with pancreatic insufficiency, no specific CFTR mutations have been found to determine MI (refs 3,4). A familial recurrence rate of 29% suggests that other genetic factors are involved in the expression of the MI phenotype5. No independent correlation between CFTR genotype and CF lung disease has been described, indicating that the extreme variability in the lung phenotype is also determined by modifier genes and environmental factors.

We previously identified a CF modifier locus mapped to the proximal region of mouse chromosome 7 that modulated the generally fatal intestinal disease in homozygous mutant mice6. In this report, we demonstrate the existence of a similar CF modifier gene on human chromosome 19, in a region syntenic to the mouse locus7.

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Acknowledgements

We thank C. Henshaw, F. Gilbert and J. Li for blood collection/extraction from CF patients and N. Cobos, C. Vazquez, J. Ferrer-Calvette and J. Perez-Frias for providing clinical data from CF patients. This work was supported by: NIH grant P50 DK49096-05 and Canadian Genetic Diseases Network (L.-C.T.); IGA MZ CR grants 2899-5, 3526-3 and 4124-3 (M.M. Jr); FIS grant 96/2005 (T.C. and X.E.); and National Center for Research Resources grant M01-RR00064 -GCRC DNA Core Laboratory (B.M.).

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Authors and Affiliations

  1. Research Institute, The Hospital for Sick Children , Toronto, Ontario, Canada

    Julian Zielenski, Mary Corey, Richard Rozmahel, Danuta Markiewicz, Isabel Aznarez, Peter Durie & Lap-Chee Tsui

  2. Department of Public Health Sciences, University of Toronto, Ontario, Canada

    Mary Corey

  3. Department of Pharmacology, University of Toronto, Ontario, Canada

    Richard Rozmahel

  4. Medical and Molecular Genetics Center-IRO, Hospital Duran i Reynals, L'Hospitalet, Barcelona, Catalonia , 08907, Spain

    Teresa Casals, Sara Larriba & Xavier Estivill

  5. Centre de Biogénétique, CHU, UBO, ETSBO , Brest, France

    Bernard Mercier & Claude Ferec

  6. Department of Pediatrics, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore , 21287-3914, Maryland, USA

    Garry R. Cutting

  7. Department of Molecular Genetics-CF Center, Institute of Biology and Medical Genetics, University Hospital Prague Motol, V. Uvalu 84, Praha 5, CZ 15006, Czech Republic

    Alice Krebsova & Milan Macek Jr

  8. The Cystic Fibrosis Center, Saint Vincent's Hospital and Medical Center of New York, 36 Seventh Avenue, Suite 509 , New York, 10011, New York, USA

    Elinor Langfelder-Schwind & J. DeCelie-Germana

  9. Intermountain Cystic Fibrosis Center, University of Utah, Salt Lake City, 84132, Utah, USA

    Bruce C. Marshall

  10. Laboratoire de Biochimie Génétique, Institut de Biologie, Boulevard Henri IV, Montpellier CEDEX, 34060 , France

    Mirreille Claustres

  11. Centro de Analisis Geneticos, Zaragoza , Spain

    Ana Palacio

  12. Department of Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland

    Jerzy Bal & Aleksandra Nowakowska

  13. Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada

    Peter Durie

  14. Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada

    Lap-Chee Tsui

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  1. Julian Zielenski
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Correspondence to Lap-Chee Tsui.

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Zielenski, J., Corey, M., Rozmahel, R. et al. Detection of a cystic fibrosis modifier locus for meconium ileus on human chromosome 19q13. Nat Genet 22, 128–129 (1999). https://doi.org/10.1038/9635

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