Fanconi anemia (FA) is a rare autosomal recessive disease characterized by progressive pancytopenia, congenital malformations, and predisposition to acute myeloid leukemia. Fanconi anemia is genetically heterogeneous, with at least eight distinct complementation groups of FA (A, B, C, D1, D2, E, F, and G) having been defined by somatic cell fusion studies. Six genes (FANCA, FANCC, FANCD2, FANCE, FANCG, and FANCF) have been cloned. Mutations of the seventh Fanconi anemia gene, BRCA2, have been shown to lead to FAD1 and probably FAB groups. In order to characterize the molecular defects underlying FA in Tunisia, 39 families were genotyped with microsatellite markers linked to known FA gene. Haplotype analysis and homozygosity mapping assigned 43 patients belonging to 34 families to the FAA group, whereas one family was probably not linked to the FANCA gene or to any known FA genes. For patients belonging to the FAA group, screening for mutations revealed four novel mutations: two small homozygous deletions 1693delT and 1751-1754del, which occurred in exon 17 and exon 19, respectively, and two transitions, viz., 513G fi A in exon 5 and A fi G at position 166 (IV-S24+166A fi G) of intron 24. Two new polymorphisms were also identified in intron 24 (IVS24-5G/A and IVS24-6C/G).

Transgressive palmoplantar keratoderma (PPK) is the phenotypic hallmark of Mal de Meleda (MDM, MIM 24300). It is characterized by erythema and hyperkeratosis that extend to the dorsal face of the hands and feet. The disease is distributed worldwide and includes the Mediterranean population. The gene responsible for MDM, ARS (component B) mapped on chromosome 8qter, encodes for the SLURP-1 protein (Ly-6/uPAR related protein-1). A variety of mutations within the ARS gene have been shown to underlie MDM in different populations. Genetic heterogeneity of MDM is suspected. We have recently shown that three different homozygous mutations (82delT, C77R, C99Y) were responsible for MDM in 17 patients from Northern Tunisia belonging to eight unrelated consanguineous families. We report here a Tunisian family with three siblings presenting with recessive transgressive PPK closely resembling the MDM phenotype that excludes linkage to the ARS gene.

The results suggest that the ARS gene is likely to be responsible for MDM in the eight Tunisian families. The clinical variability in the expression of PPK in MDM Tunisian patients might be accounted for by the intervention of modifier genes influencing the MDM phenotype.

Megaloblastic anaemia 1 (MGA1) is a rare autosomal recessive condition characterized by selective intestinal vitamin B12 malabsorption and proteinuria. More than 200 MGA1 patients have been identified worldwide, but the disease is relatively prevalent in Finland, Norway and several Eastern Mediterranean regions. MGA1 is genetically heterogeneous and can be caused by mutations in either the cubilin (CUBN) or the amnionless (AMN) gene. In the present study we investigated the molecular defect underlying MGA1 in nine Tunisian patients belonging to six unrelated consanguineous families. Haplotype and linkage analyses, using microsatellite markers surrounding both CUBN and AMN genes, indicated that four out of the six families were likely to be linked to the CUBN gene. Patients from these families were screened for the Finnish, Mediterranean and Arabian mutations already published. None of the screened mutations could be detected in our population. One family showed a linkage to AMN gene. Direct screening of the AMN gene allowed the identification of the c.208-2A>G mutation, previously described in a Jewish Israeli patient of Tunisian origin and in Turkish patients. This suggests that the c.208-2A>G mutation may derive from a single Mediterranean founder ancestor. For the last family, haplotype analysis excluded both CUBN and AMN genes, suggesting the existence of a third locus that may cause MGA1.

Lysinuric protein intolerance (LPI, MIM# 222700) is an inherited aminoaciduria caused by defective transport of cationic amino acids (CAAs; arginine, lysine, ornithine) at the basolateral membrane of epithelial cells in the intestine and kidney. We report the first prenatal diagnosis by direct mutational analysis of LPI performed in a Tunisian family. An amniotic fluid sample was carried out at 16 weeks of gestation in a 32-year-old Tunisian woman who consulted for prenatal diagnosis. The 1471 delTTCT mutation at homozygous state was identified indicating that the fetus was affected by LPI. The identification of this specific mutation provides a tool, which can be easily applied in Tunisia for molecular diagnosis, genetic counseling, and prenatal diagnosis of LPI.