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Genetic Heterogeneity of Megaloblastic Anaemia Type 1 in Tunisian Patients

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Genetic Heterogeneity of Megaloblastic Anaemia Type 1 in Tunisian Patients J Hum Genet (2007) 52:262–270 DOI 10.1007/s10038-007-0110-0 ORIGINAL ARTICLE Genetic heterogeneity of megaloblastic anaemia type 1 in Tunisian patients Chiraz Bouchlaka Æ Chokri Maktouf Æ Bahri Mahjoub Æ Abdelkarim Ayadi Æ M. Tahar Sfar Æ Mahbouba Sioud Æ Neji Gueddich Æ Zouheir Belhadjali Æ Ahmed Rebaı¨ Æ Sonia Abdelhak Æ Koussay Dellagi Received: 2 August 2006 / Accepted: 21 December 2006 / Published online: 7 February 2007 Ó The Japan Society of Human Genetics and Springer 2007 Abstract Megaloblastic anaemia 1 (MGA1) is a rare geneous and can be caused by mutations in either the autosomal recessive condition characterized by selec- cubilin (CUBN) or the amnionless (AMN) gene. In tive intestinal vitamin B12 malabsorption and pro- the present study we investigated the molecular defect teinuria. More than 200 MGA1 patients have been underlying MGA1 in nine Tunisian patients belonging identified worldwide, but the disease is relatively to six unrelated consanguineous families. Haplotype prevalent in Finland, Norway and several Eastern and linkage analyses, using microsatellite markers Mediterranean regions. MGA1 is genetically hetero- 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 fami- C. Bouchlaka Á C. Maktouf Á S. Abdelhak (&) lies were screened for the Finnish, Mediterranean and Molecular Investigation of Genetic Orphan Diseases, Arabian mutations already published. None of the Institut Pasteur de Tunis, BP 74, 13 Place Pasteur 1002, screened mutations could be detected in our popula- Tunis Belve´de`re, Tunisia tion. One family showed a linkage to AMN gene. e-mail: [email protected] Direct screening of the AMN gene allowed the C. Maktouf identification of the c.208-2A>G mutation, previously Nuclear Medicine Group, Institut Pasteur de Tunis, Tunis, described in a Jewish Israeli patient of Tunisian origin Tunisia and in Turkish patients. This suggests that the c.208- B. Mahjoub Á A. Ayadi Á M. T. Sfar 2A>G mutation may derive from a single Mediter- Department of Paediatrics, C.H.U. Tahar Sfar, Mahdia, ranean founder ancestor. For the last family, haplo- Tunisia type analysis excluded both CUBN and AMN genes, suggesting the existence of a third locus that may M. Sioud Department of Paediatrics, Hoˆ pital d’Enfants, Tunis, cause MGA1. Tunisia Keywords Megaloblastic anaemia Á Imerslund- N. Gueddich Gra¨sbeck syndrome Á Haplotype analysis Á Department of Paediatrics, C.H.U., Monastir, Tunisia Consanguinity Á Genetic heterogeneity Á Mutation Z. Belhadjali screening Department of Haematology, C.H.U., Aziza Othmana, Tunis, Tunisia A. Rebaı¨ Introduction Centre de Biotechnologie de Sfax, Sfax, Tunisia Megaloblastic anaemia in children is mainly due to K. Dellagi folate or vitamin B12 (Vit B12) deficiency. Inherited Department of Haematology and Laboratory of Immunology, Vaccinology and Molecular Genetics, Institut causes of Vit B12 malabsorption can be related to (1) a Pasteur de Tunis, Tunis, Tunisia lack or low secretion of gastric intrinsic factor (IF) 123 J Hum Genet (2007) 52:262–270 263 (known as pernicious anaemia, MIM 261000), or (2) a encodes for cubilin, a multi-ligand receptor essential deficiency of transcobalamin II (known as TCII defi- for the uptake of Vit B12 in the small intestine (Birn ciency, MIM 275350), or (3) a defect in selective up- et al. 1997). take of the intrinsic factor–vitamin B12 (IF-Vit B12) In all Finnish families the disease is caused by complex in the terminal ileum (known as megaloblastic mutations in the CUBN gene, with one founder anaemia 1, MGA1, MIM 261100). mutation, P1297L, accounting for the majority of Megaloblastic anaemia 1 (MGA1), known as Finnish cases (Aminoff et al. 1999; Tanner et al. Imerslund–Gra¨sbeck syndrome, (I-GS) is a rare 2004). autosomal recessive condition originally and inde- However, not all I-GS patients have CUBN muta- pendently described by Imerslund in Norway tions. Through linkage studies of Norwegian and (Imerslund 1960) and Gra¨sbeck and collaborators in Middle Eastern kindreds (Aminoff et al. 1999; Al- Finland (Gra¨sbeck et al. 1960). At the cellular level Alami et al. 2002) a second candidate gene, AMN, was the disease is a selective intestinal Vit B12 malab- identified and was located on human chromosome sorption defect that is characterized by the frequent 14q32 (Tanner et al. 2003). Distinct mutations were association of juvenile megaloblastic anaemia and a identified in the AMN gene in Norwegian, Jewish, benign proteinuria of the tubular type (Gra¨sbeck Turkish and Saudi Arabian families (Tanner et al. 1972; Wahlstedt-Froberg et al. 2003). Patients have 2003, 2004). In Norway, all the studied cases were due decreased levels of serum Vit B12 in the presence of to mutations in the AMN gene, whereas cases from normal levels of intrinsic factor (IF) (Mackenzie et al. Mediterranean regions had mutations in either the 1972; Burman et al. 1985). Classically, patients pres- CUBN or the AMN gene (Tanner et al. 2004). It has ent during childhood with pallor, developmental de- been demonstrated that AMN functions in the same lays and variable neurological symptoms (Campbell pathway as cubilin and forms a complex designated et al. 1981; Broch et al. 1984; Salameh et al. 1991; cubam, which is essential for endocytosis/trancytosis of Wulffraat et al. 1994; Altay et al. 1995; Carmel et al. several ligands (Fyfe et al. 2004). 2003). The therapy consists of periodic parenteral In the present study we report on the first genetic administration of Vit B12 that restores normal and molecular investigations of MGA1 in a North metabolism and haematopoiesis. African population and, particularly, in Tunisian fam- Currently, more than 200 human MGA1 cases have ilies. For this purpose, linkage analysis and homozy- been reported worldwide, but the disease occurs more gosity mapping were performed in six unrelated frequently in Scandinavian countries: Norway and consanguineous families, including nine patients. Our Finland (Tanner et al. 2004). The disease is also fre- data showed evidence for linkage in four families to the quent in several Middle Eastern countries, including MGA1 locus and in one family to the AMN gene. Turkey, Kuwait, Saudi Arabia and Israel (Ben-Bassat Mutation screening by direct sequencing of all exons of et al. 1969; Yetgin et al. 1983; Abdelaal and Ahmed the AMN gene allowed the identification of the c.208- 1991; Salameh et al. 1991; Altay et al. 1995; Celep 2A>G, a mutation recently reported in a Jewish Israeli et al. 1996; Ismail et al. 1997; Tanner et al. 2004). In patient of Tunisian origin. In one multiplex family, Tunisia, 24 cases have been diagnosed, but only some haplotype analysis excluded linkage to both CUBN have been published (el Bez et al. 1992; Ben Meriem and AMN genes, suggesting the presence of a third et al. 1993; Fitouri et al. 2001). gene locus that may cause MGA1. In humans, MGA1 exhibits locus heterogeneity and can be caused by mutations in at least two different genes, cubilin (CUBN) (Aminoff et al. 1999) and am- Patients and methods nionless (AMN) (Tanner et al. 2003). The MGA1 was the first locus to be mapped by linkage analysis in Patients and families Finnish and Norwegian families to a 6 cM region on chromosome 10p12.1 (Aminoff et al. 1995). A func- Six unrelated MGA1 families, referred to here as tional candidate gene encoding the intrinsic factor– families MA1 to MA6, with a total of nine patients and vitamin B12 (IF-VitB12) receptor, cubilin, has been 19 unaffected family members, were investigated. isolated by positional cloning (Moestrup et al. 1998), Consanguinity occurred in all families and was of first and the human gene, CUBN, was mapped to the same or second degree. All patients were female. Three chromosomal region within the MGA1 locus (Kozy- families (MA1, MA5 and MA6) were multiplex, with raki et al. 1998). Mutations within the CUBN gene two affected siblings; two families (MA2 and MA4) have been shown to be the cause of MGA1. This gene were simplex, with one affected and at least one 123 264 J Hum Genet (2007) 52:262–270 healthy child; and one singleton family (MA3) with Methods only one affected child. Pedigrees of these families are shown in Fig. 1. Families MA1, MA2, MA3 and MA6 Genotyping had originated from central Tunisia; two of them (MA1 and MA2) were from the same city; and two families, Informed consent was obtained from all families. MA4 and MA5, had originated from cities in northern Genomic DNA was extracted from peripheral blood Tunisia. leucocytes from all patients and unaffected relatives by Patients were diagnosed on the basis of the associ- standard procedures (Sambrook et al. 1989). Micro- ation of clinical symptoms, low serum Vit B12 level satellite markers D10S1476, D10S504, CUBN and and normal folate level in vitamins assays assessed by D10S1714 have been amplified for linkage analysis at radioimmunoassay methods (Simultrac, SNB–ICN 10p12.1. CUBN is an intragenic marker (Aminoff et al. pharmaceuticals). The diagnosis was confirmed by the 1999). Microsatellites D14S1006, D14S985, D14S293 radiolabelled cobalamin absorption test with and and D14S292 localized within the AMN gene were without adjunction of exogenous intrinsic factor (dual- employed for the chromosomal segregation study at isotope Schilling test, Dicopac test) (Schilling 1953). 14q32, and markers D2S2345, D2S2284 and D4S1614, Patients with MGA1 did not correct their intestinal D4S3023 and D4S394 for linkage analysis to the LRP2 malabsorption with exogenous IF. The outcome of the (megalin) and LRPAP1 genes (RAP) at chromosomes disease is always favourable under regular parenteral 2q31.1 and 4p16.3, respectively. The polymorphic Vit B12 administration. markers overlapping each locus tested (interval of Fig. 1 Pedigrees and haplotype analysis of the six I- GS Tunisian families with four markers in a 4 cM interval overlapping the CUBN region.
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