CARBONIC-ANHYDRASE-II (CA-II) DEFICIENCY IN MAGHREBIAN PATIENTS - EVIDENCE FOR FOUNDER EFFECT AND GENOMIC RECOMBINATION AT THE CA-II LOCUS

A splice junction mutation at the exon 2 - intron 2 boundary of the ca rbonic anhydrase II (CA II) gene was previously shown to be the unique mutation underlying the CA II deficiency syndrome in patients of Arab descent. Fourteen Tunisian (Maghrebian) families with a history of os teopetrosis, renal tubular acidosis, mental retardation, and CA II def iciency were studied to test the hypothesis that the mutation, found i n all 24 patients, derived from a common ancestor originating in the A rabic Peninsula. A filiation study permitted us to trace these familie s back to a common Arabic tribe that settled in the Maghreb in the ten th century, indicating a common ethnic origin for these families. Segr egation of the mutation with a TaqI biallelic restriction site polymor phism upstream of the CA II gene was studied by sequence-tagged site a nalysis in all the family members. These studies showed cosegregation of the Tag (-) allele with the mutation in 12 families out of 14. This observation supports a founder effect to explain the common CA LT def iciency allele in this population. In the remaining two families, a ge nomic recombination or gene conversion occurred between the TaqI restr iction marker and the mutation causing the disease. The relatively hig h recombination frequency suggests the presence of a hot spot for reco mbination or gene conversion at the CA LI locus.