Mapping of three novel loci for non-syndromic autosomal recessive mental retardation (NS-ARMR) in consanguineous families from Pakistan.

To date, of 13 loci with linkage to non-syndromic autosomal recessive mental retardation (NS-ARMR), only six genes have been established with associated mutations. Here we present our study on NS-ARMR among the Pakistani population, where people are traditionally bound to marry within the family or the wider clan. In an exceptional, far-reaching genetic survey we have collected more than 50 consanguineous families exhibiting clinical symptoms/phenotypes of NS-ARMR. In the first step, nine families (MR2-9 and MR11) with multiple affected individuals were selected for molecular genetic studies. Two families (MR3, MR4) showed linkage to already know NS-ARMR loci. Fifteen affected and 10 unaffected individuals from six (MR2, MR6, MR7, MR8, MR9 and MR11) families were genotyped by using Affymetrix 5.0 or 6.0 single-nucleotide polymorphism (SNP) microarrays. SNP microarray data was visually inspected by dChip and genome-wide homozygosity analysis was performed by HomozygosityMapper. Additional mapping was performed (to exclude false-positive regions of homozygosity called by HomozygosityMapper and dChip) on all available affected and unaffected members in seven NS-ARMR families, using microsatellite markers. In this manner we were able to map three novel loci in seven different families originating from different areas of Pakistan. Two families (MR2, MR5) showed linkage on chromosome 2p25.3-p25.2. Three families (MR7, MR8, and MR9) that have been collected from the same village and belong to the same clan were mapped on chromosome 9q34.3. MR11 maps to a locus on 9p23-p13.3. Analysis of MR6 showed two positive loci, on chromosome 1q23.2-q23.3 and 8q24.21-q24.23. Genotyping in additional family members has so far narrowed, but not excluded the 1q locus. In summary, through this study we have identified three new loci for NS-ARMR, namely MRT14, 15 and 16.

A comprehensive study on the major mutations in glucose-6-phosphate dehydrogenase-deficient polymorphic variants identified in the coastal provinces of Caspian Sea in the north of Iran.

BACKGROUND: The aim of this study was the molecular analysis of G6PD patients for G6PD mutations in the coastal provinces of the Caspian Sea in north of Iran. METHODS: Studies on G6PD deficiency in the coastal provinces of the Caspian Sea in Iran were performed in 248 patients with a history of favism, in Mazandaran, Golestan and Gillan provinces, which contributed 74, 71 and 103 samples, respectively. Three different major polymorphic variants were determined by molecular analysis, using SSCP, sequencing and PCR-RFLP methods. Firstly, all Mazandaranian samples were searched for the Mediterranean mutation by PCR-RFLP method. The remaining samples of the Mazandaran province were analysed by SSCP followed by sequencing for other mutations. Then, our research was expanded in two other provinces, Golestan and Gillan, by the PCR-RFLP method. RESULTS: Three different major polymorphic variants were found: G6PD Mediterranean 75.4% (187 out of 248), G6PD Chatham 19.76% (49 out of 248), G6PD Cosenza 2.02% (5 out of 248) and 7 samples out of 248 remained unknown. Also, there was no significant difference in the incidence of various G6PD polymorphic variants with mean age, and various blood work values such as Hb, WBC and MCV between two major variants (p>0.20). CONCLUSIONS: These results which are the first molecular investigation in north of Iran indicate a higher prevalence of G6PD Chatham in this large Iranian population than anywhere else in the world. The distribution of these G6PD variants is more similar to that found in an Italian population (80-84% for Mediterranean, 20% for Chatham and 1.9% for Cosenza mutation). Although the origin of Iranian population is rather uncertain, the closer similarity of the mutation spectrum to Italian rather than Middle Eastern population may indicate that these populations have a common ancestral origin.