Carbonic anhydrase II (CA II) deficiency in Maghrebian patients: evidence for founder effect and genomic recombination at the CA II locus

Abstract

A splice junction mutation at the exon 2-intron 2 boundary of the carbonic 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 osteopetrosis, renal tubular acidosis, mental retardation, and CA II deficiency were studied to test the hypothesis that the mutation, found in all 24 patients, derived from a common ancestor originating in the Arabic Peninsula. A filiation study permitted us to trace these families back to a common Arabic tribe that settled in the Maghreb in the tenth century, indicating a common ethnic origin for these families. Segregation of the mutation with a TaqI biallelic restriction site polymorphism upstream of the CA II gene was studied by sequence-tagged site analysis in all the family members. These studies showed cosegregation of the Taq (-) allele with the mutation in 12 families out of 14. This observation supports a founder effect to explain the common CA II deficiency allele in this population. In the remaining two families, a genomic recombination or gene conversion occurred between the TaqI restriction marker and the mutation causing the disease. The relatively high recombination frequency suggests the presence of a hot spot for recombination or gene conversion at the CA II locus.

A phenocopy of CAII deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis

“…18 19 The commonest of these, colloquially known as the Arabic mutation, leads to loss of the donor splice junction of intron 2. 20 It accounts for almost all cases in North Africa and the Arabian peninsula, which comprise 75% of all those reported. An interesting study found that affected families were all descended from the same nomadic tribe (Helal) in the 10th century.…”

Hereditary Distal Renal Tubular Acidosis: New Understandings

“…In 1996, Fathallah et al analyzed 14 Tunisian families (24 patients) for segregation of a TaqI biallelic marker located upstream of the CAII gene (45). In 12 families, analysis of TaqI(−) marker segregation showed allelic association with CAII deficiency with no evidence of recombination between the TaqI allele and the CAII mutation site.…”

“…The CAII deficiency syndrome has been reported to be particularly common in Arab populations of the Middle East (44). More than 70% of the reported cases of CAII deficiency syndrome are from this part of the world, probably the result of both a high rate of consanguineous marriages and an increased frequency of the CAII-deficiency allele in Arab populations (45).…”

Unraveling the molecular basis of hereditary renal tubular acidosis

“…[17][18][19][20][21][22] A missense mutation (TAT AE TAT), which results in the amino acid substitution of tryptophan (Trp) for histidine (His) at position 107, has been described in several families with a relatively high frequency of skeletal fractures and absence of mental retardation. A splice junction mutation at the 5Ј end of intron 12 is detected in most patients of Arabic descent.…”