Said Al-Yahyaee

A novel locus for hereditary spastic paraplegia with thin corpus callosum and epilepsy

Background: Hereditary spastic paraplegia (HSP) are classified clinically as pure when progressive spasticity occurs in isolation or complicated when other neurologic abnormalities are present. At least 22 genetic loci have been linked to HSP, 8 of which are autosomal recessive (ARHSP). HSP complicated with the presence of thin corpus callosum (HSP-TCC) is a common subtype of HSP. One genetic locus has been identified on chromosome 15q13-q15 (SPG11) for HSP-TCC, but some HSP-TCC families have not been linked to this locus. Methods: The authors characterized two families clinically and radiologically and performed a genome-wide scan and linkage analysis. Results: The two families had complicated ARHSP. The affected individuals in Family A had thin corpus callosum and mental retardation, whereas in Family B two of three affected individuals had epilepsy. In both families linkage analysis identified a locus on chromosome 8 between markers D8S1820 and D8S532 with the highest combined lod score of 7.077 at marker D8S505. This 9 cM interval located on 8p12-p11.21 represents a new locus for ARHSP-TCC. Neuregulin and KIF13B genes, located within this interval, are interesting functional candidate genes for this HSP form. Conclusion: Two consanguineous families with complicated autosomal recessive hereditary spastic paraplegia were clinically characterized and genetically mapped to a new locus on 8p12-p11.21.

Interleukin-1β gene (IL-1B) and interleukin 1 receptor antagonist gene (IL-1RN) polymorphisms and gastric cancer risk in an Omani Arab population

BackgroundGastric cancer (GC) is the most common malignancy in Oman. Interleukin-1β gene (IL-1B) and interleukin-1 receptor antagonist gene (IL-1RN) polymorphisms have been associated with increased GC risk. No previous studies have examined their role in an Arab population. We tested the associations between polymorphisms of IL1B at positions −31, −511, and +3954 and the IL-1RN polymorphism [variable number of tandem repeats (VNTR) and TC polymorphism at the −2018 position] and GC in Omani Arab patients.MethodsGenomic DNA was extracted from peripheral blood of 245 control subjects and 118 gastric cancer patients. The DNA samples were analyzed using the TaqMan allelic discrimination test for IL-1B −31, −511, and +3954 polymorphisms and IL-1RN −2018 polymorphism. The VNTR of IL-1RN was genotyped using the polymerase chain reaction followed by agarose gel electrophoresis.ResultsThere was an association between the presence of IL-1RN*2 allele and gastric cancer [odds ratio (OR) = 2.2, 95% confidence interval (CI) = 1.0–3.3, P = 0.04). The GC risk further increased to OR = 3.5 (95% CI = 1.0–11.9) in Helicobacter pylori-positive patients. No association was found between any of the other polymorphisms studied and GC.ConclusionIL-1RN polymorphism increased the risk of GC in an Omani Arab population, consistent with previous reports. In contrast, the IL-1B −31 polymorphism was not associated with an increased GC risk. These findings underscore the role of cytokine gene polymorphisms in the development of GC and further support the ethnic differences in the effect of IL-1B polymorphism on GC carcinogenesis.

Clinical and molecular analysis of Grebe acromesomelic dysplasia in an Omani family

Grebe syndrome is a rare autosomal recessive acromesomelic dysplasia. The syndrome was studied clinically, radiographically, and genetically in an Omani family with four affected children. The affected persons had normal axial skeletons, severely shortened, and deformed limbs with severity increasing in a proximo‐distal gradient, and subluxated joints. The humeri and femora were hypoplastic with distal malformations. The radii/ulnae were shortened and deformed whereas carpal bones were invariably rudimentary or absent. The tibiae appeared rudimentary; fibulae were absent in two children, and some tarsal and metatarsal bones were absent. The proximal and middle phalanges were absent while the distal phalanges were present. The father and mother had short first metacarpal and middle phalynx of the fifth finger and hallux valgus respectively. Transition A1137G and deletion delG1144 mutations in the gene encoding the cartilage‐derived morphogenetic protein‐1 (CDMP‐1) were identified in this family. The A1137G is a silent mutation coding for lysine, whereas the delG1144 predicts a frameshift mutation resulting in a presumable loss of the CDMP‐1 biologically active carboxy‐terminal domain. The affected siblings were homozygous for the delG1144 mutation while parents were heterozygous.

Association of adiponectin promoter variants with traits and clusters of metabolic syndrome in Arabs: Family-based study

Plasma levels of adiponectin are decreased in type 2 diabetes, obesity and hypertension. Our aim was to use a family-based analysis to identify the genetic variants of the adiponectin (ADIPOQ) gene that are associated with obesity, insulin resistance, dyslipidemia and hypertension, among Arabs. We screened 328 Arabs in one large extended family for single nucleotide polymorphisms (SNPs) in the promoter region of the ADIPOQ gene. Two common SNPs were detected: rs17300539 and rs266729. Evidences of association between traits related to the metabolic syndrome and the SNPs were studied by implementing quantitative genetic association analysis. Results showed that SNP rs266729 was significantly associated with body weight (p-value=0.001), waist circumference (p-value=0.037), BMI (p-value=0.015) and percentage of total body fat (p-value=0.003). Up to 4.1% of heritability of obesity traits was explained by the rs266729 locus. Further cross-sectional analysis showed that carriers of the G allele had significantly higher values of waist circumference, BMI and percentage of total body fat (p-values 0.014, 0.004 and 0.032, respectively). No association was detected between SNP rs266729 and other clusters of metabolic syndrome or their traits except for HOMA-IR and fasting plasma insulin levels, p-values 0.035 and 0.004, respectively. In contrast, both measured genotype and cross-sectional analysis failed to detect an association between the SNP rs17300539 with traits and clusters of metabolic syndrome. In conclusion, we showed family-based evidence of association of SNP rs266729 at ADIPOQ gene with traits defining obesity in Arab population. This is important for future prediction and prevention of obesity in population where obesity is in an increasing trend.

Association of gene variants with susceptibility to type 2 diabetes among Omanis

AIM To investigate the association of 10 known common gene variants with susceptibility to type 2 diabetes mellitus (T2D) among Omanis. METHODS Using case-control design, a total of 992 diabetic patients and 294 normoglycemic Omani Arabs were genotyped, by an allelic discrimination assay-by-design TaqMan method on fast real time polymerase chain reaction system, for the following gene variants: KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398), CDKN2A/B (rs10811661), FTO (rs9939609 and rs8050136), IGF2BP2 (rs4402960), SLC30A8 (rs13266634) CAPN10 (rs3792267) and HHEX (rs1111875). T2D patients were recruited from the Diabetes Clinic (n = 243) and inpatients (n = 749) at Sultan Qaboos Univesity Hospital (SQUH), Muscat, Oman. Adult control participants (n = 294) were volunteers from the community and from those visiting Family Medicine Clinic at SQU, for regular medical checkup. The difficulty in recruiting Omani participants with no family history of diabetes was the main reason behind the small number of control participants in this study. Almost all volunteers questioned had a relative with diabetes mellitus. Inspite of the small number of normoglycemic controls in this study, this sample was sufficient for detection of genes and loci for common alleles influencing T2D with an odds ratio of ≥ 1.3 reaching at least 80% power. Data was collected from June 2010 to February 2012. RESULTS Using binary logistic regression analysis, four gene variants showed significant association with T2D risk: KCNJ11 (rs5219, P = 5.8 × 10(-6), OR = 1.74), TCF7L2 (rs7903146, P = 0.001, OR = 1.46), CDKAL1 (rs10946398, P = 0.002, OR = 1.44) and CDKN2A/B (rs10811661, P = 0.020, OR = 1.40). The fixation index analysis of these four gene variants indicated significant genetic differentiation between diabetics and controls {[KCNJ11 (rs5219), P < 0.001], [TCF7L2 (rs7903146), P < 0.001], [CDKAL1 (rs10946398), P < 0.05], [CDKN2A/B (rs10811661), P < 0.05]}. The highest genotype variation % between diabetics and controls was found at KCNJ11 (2.07%) and TCF7L2 (1.62%). This study was not able to detect an association of T2D risk with gene variants of IGF2BP2 (rs4402960), SLC30A8 (rs13266634), CAPN10 (rs3792267) and HHEX (rs1111875). Moreover, no association was found between FTO gene variants (rs9939609 and rs8050136) and T2D risk. However, T2D risk was found to be significantly associated with obesity (P = 0.002, OR = 2.22); and with the Waist-to-Hip ratio (n = 532, P = 1.9 ×10(-7), OR = 2.4), [among males (n = 234, P = 1.2 × 10(-4), OR = 2.0) and females (n = 298, P = 0.001, OR = 6.3)]. CONCLUSION Results confirmed the association of KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398) and CDKN2A/B (rs10811661) gene variants with susceptibility to T2D among Omani Arabs.

Novel Mutation of GLRA1 in Omani Families With Hyperekplexia and Mild Mental Retardation

Hyperekplexia is characterized by neonatal hypertonia and exaggerated startle reflex in response to loud noise or tactile stimuli. Mutations in patients with hyperekplexia were evident in several genes encoding proteins involved in glycinergic neurotransmission, i.e., glycine receptor α and β subunits, collybistin, gephyrin, and glycine transporter 2. We clinically and genetically characterized two large, unrelated consanguineous families with hyperekplexia. Affected members of the two families manifested hyperekplexia with mild mental retardation. Patients exhibited a novel homozygote c.593G>C missense mutation in GLRA1, resulting in amino acid substitution p.W170S in the corresponding mature glycine receptor α1 subunit. This mutation was absent in 400 randomly selected chromosomes in the same population. In conclusion, a novel p.W170S mutation in the extracellular ligand binding domain of glycine receptor α1 subunit was detected in patients with hyperekplexia and mild mental retardation.

Apolipoprotein A1 Gene Polymorphisms at the - 75 bp and + 83/84 bp Polymorphic Sites in Healthy Omanis Compared with World Populations

The relative frequencies of the *A allele of the APOA1 gene at - 75 bp (M1 -) and the C or T +83/+84 bp allele (M2 -) varied significantly between populations. We found the frequencies of M1 - and M2 - to be 0.22 and 0.067, respectively, in 150 healthy Omanis. These frequencies were compared to frequencies found in other world populations.

Distribution of Apolipoprotein E Alleles in the Omani Population

Objective: To estimate the apolipoprotein E (apo E) allele distribution in the Omani population and to compare them with those of other populations. Subjects and Methods: One hundred and sixty-two healthy Omanis of Arab Bedouin origin were genotyped by polymerase chain reaction followed by restriction fragment length polymorphism. Results: The apo E allele frequencies were: ε2, 0.052; ε3, 0.886; ε4, 0.062. This pattern of distribution, characterized by the lowest ε4 and among the highest ε3 allele frequencies in the world, was very similar to that of Arabs, Southern Europeans of the Mediterranean basin, Indians, and Japanese populations. Conclusion: The results indicate that the allelic distribution of apo E in healthy Omanis is characterized by low Apo ε4 and high ε3 allele frequencies similar to those of other Arab, Southern European, Japanese and Indian populations. The homogeneous distribution of apo E alleles in this group of populations might have been influenced by diet and/or genetic admixture.

Pelizaeus-Merzbacher–Like Disease in a Family With Variable Phenotype and a Novel Splicing GJC2 Mutation

Pelizaeus-Merzbacher–like disease is an autosomal recessive disorder characterized by neonatal nystagmus, ataxia, progressive spasticity, and development delay and is rarely caused by GJC2 mutations. We report 7 patients from a large consanguineous family who had variable severity of Pelizaeus-Merzbacher–like disease. The 3 youngest of branch A were bedridden by their first year because of permanent scissoring of their legs and had severe frontal lobe epilepsy. The single patient from branch B was the least affected, being able to walk until 12 years of age and had no epilepsy. Brain magnetic resonance imaging (MRI) showed hypomyelination. The patients had a novel canonical splicing GJC2 c.-20+1G>C mutation with a predicted loss of the coding connexin 47 protein. The exceptionally large number of patients in this unique family enabled to describe the intrafamilial variability of Pelizaeus-Merzbacher–like disease. The predicted functional loss of connexin 47 might be associated with a severe form of Pelizaeus-Merzbacher–like disease.

The Effect of Residing Altitude on Levels of High-Density Lipoprotein Cholesterol: A Pilot Study From the Omani Arab Population.

Lower mortality rates from coronary heart disease and higher levels of serum high-density lipoprotein cholesterol (HDL-C) have been observed in populations residing at high altitude. However, this effect has not been investigated in Arab populations, which exhibit considerable genetic homogeneity. We assessed the relationship between residing altitude and HDL-C in 2 genetically similar Omani Arab populations residing at different altitudes. The association between the levels of HDL-C and other metabolic parameters was also investigated. The levels of HDL-C were significantly higher in the high-altitude group compared with the low-altitude group. Stepwise regression analysis showed that altitude was the most significant factor affecting HDL-C, followed by gender, serum triglycerides, and finally the 2-hour postprandial plasma glucose. This finding is consistent with previously published studies from other populations and should be taken into consideration when comparing cardiovascular risk factors in populations residing at different altitudes.