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Human Molecular Genetics, 2002, Vol. 11, No. 26 3273-3281
© 2002 Oxford University Press

Cell complementation using Genebridge 4 human:rodent hybrids for physical mapping of novel mitochondrial respiratory chain deficiency genes

Pascale de Lonlay1, Claude Mugnier2, Damien Sanlaville3, Karine Chantrel-Groussard1, Paule Bénit1, Sophie Lebon1, Dominique Chrétien1, Noman Kadhom1, Safa Saker4, Gabor Gyapay4, Serge Romana3, Jean Weissenbach5, Arnold Munnich1, Pierre Rustin1 and Agnès Rötig1,*

1Unité de Recherches sur les Handicaps Génétiques de l'Enfant (INSERM U393), 2Service Informatique, 3Service de Cytogénétique, Hôpital Necker-Enfants Malades, Paris, 4Généthon, Evry and 5Centre National de Séquençage, Evry, France

Received July 29, 2002; Accepted October 19, 2002

The mapping and identification of respiratory chain deficiency genes is particularly tedious owing to the large number of genes encoding catalytic subunits and involved in respiratory chain (RC) assembly and maintenance. We have developed a functional complementation approach by: (i) growing the patient's fibroblasts in a highly selective medium; and (ii) transferring human chromosome fragments into RC-deficient fibroblasts by microcell-mediated transfer. In the absence of carbohydrates in the culture medium, the deficient cells rapidly disappeared unless they were rescued by a chromosome fragment carrying the disease gene. Microcells prepared from human:rodent Genebridge 4 panel of whole genome radiation hybrids were fused with fibroblast strains of two patients with complex II or I+IV deficiency and allowed to map the disease-causing genes to small intervals (4 and 12 Mb) on chromosomes 12p13 and 7p21, respectively. These intervals are similar to that obtained by genetic linkage analyses in large informative families. The recovery of normal RC enzyme activity in deficient skin fibroblasts supported the relevance of the transferred chromosome fragment in the disease. This approach makes the physical mapping of the disease genes feasible in some sporadic cases of RC deficiency.

* To whom correspondence should be addressed at: INSERM U393, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France. Tel: +33 144381584; Fax: +33 147348514; Email: roetig{at}necker.fr


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