Mohammed Nasser Al-Kindi

Heritability of Determinants of the Metabolic Syndrome among Healthy Arabs of the Oman Family Study

The metabolic syndrome, as defined by the International Diabetes Federation, was investigated in five large, extended, highly consanguineous, healthy Omani Arab families of a total of 1277 individuals. Heritability (h2) of the phenotypic abnormalities that make up the syndrome and other related traits was estimated by variance decomposition method using SOLAR software. The overall prevalence of the syndrome was 23%. The prevalence of abnormalities making the syndrome in a descending order were: obligatory waist circumference, hypertension, raised fasting blood glucose, low serum high‐density lipoprotein (HDL), and raised serum triglycerides (TGs). Highly significant, but widely spread, h2 values were obtained for: height (0.68), weight (0.68), BMI (0.68), serum HDL (0.63), serum leptin (0.55), percentage body fat (0.53), total serum cholesterol (0.53), fasting serum insulin (0.51), homeostasis model assessment‐insulin resistance index (0.48), serum TG (0.43), waist circumference (0.40), diastolic blood pressure (0.38), and 2‐hour glucose level (0.17), whereas for the metabolic syndrome itself, h2 was 0.38. The wide spread of h2 results (0.07 to 0.68) indicates that some determinants, such as weight, BMI, and HDL level, are under significant genetic influence among the Omani Arabs. Other determinants such as insulin resistance, abdominal obesity, diastolic blood pressure, and TG levels seem to be more environmentally driven.

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.

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.

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.

Disclosing the origin and diversity of Omani cattle.

Among all livestock species, cattle have a prominent status as they have contributed greatly to the economy, nutrition and culture from the beginning of farming societies until the present time. The origins and diversity of local cattle breeds have been widely assessed. However, there are still some regions for which very little of their local genetic resources is known. The present work aimed to estimate the genetic diversity and the origins of Omani cattle. Located in the south-eastern corner of the Arabian Peninsula, close to the Near East, East Africa and the Indian subcontinent, the Sultanate of Oman occupies a key position, which may enable understanding cattle dispersal around the Indian Ocean. To disclose the origin of this cattle population, we used a set of 11 polymorphic microsatellites and 113 samples representing the European, African and Indian ancestry to compare with cattle from Oman. This study found a very heterogenic population with a markedly Bos indicus ancestry and with some degree of admixture with Bos taurus of African and Near East origin.

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.

A novel missense mutation in the C2C domain of otoferlin causes profound hearing impairment in an Omani family with auditory neuropathy.

Objectives: To identify genetic defects in an Omani family diagnosed with deafness. Methods: A cross-sectional association study was conducted at the Department of Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khoud, Oman and the Centre of Medical Genetics, University of Antwerp, Antwerp, Belgium between August 2010 and September 2014. Microsatellites markers for nine non-syndromic genes were used to genotype the defective locus using the extracted DNA from family members. Sanger sequencing method was used to identify the disease causative mutation. Eazy linkage 5.05 was used to calculate the logarithm of odds score. Lasergene suite was used to detect the mutation position, and Phyre2, SMART, Rasmol, and GOR IV were used to predict the effects of the defect on protein structure and function. Results: The disease was linked to markers located on chromosome-2 and covering the OTOF (DFNB9) gene. A novel missense mutation that changed nucleotide C to G at position c.1469 and consequently the amino acid Proline to Arginine (P490R) on exon 15 was detected. Protein modeling analysis revealed the impact of the mutation on protein structure and the relevant C2C domain. The mutation seems to create a new protein isoform homologous to the complement component C1q. Conclusion: These findings suggest that the mutation found in C2C domain of the OTOF gene is likely to cause deafness in the studied family reflecting the importance of C2 domains of otoferlin in hearing loss.

Lipoprotein(a): an independent risk factor for ischemic heart disease that is dependent on triglycerides in subjects with type 2 diabetes mellitus

IntroductionLipoprotein(a) is an independent risk factor for Ischaemic Heart Disease (IHD) in the general population. There are conflicting reports in the extent of its association with IHD among subjects with Type 2 diabetes mellitus (T2DM).The aim was to determine the concentration of Lp(a) and its relationship with other lipids parameters among Omani T2DM subjects with and without IHD. An over-night fasting blood sample from 221 T2DM subjects (86 females and 135 males) and 156 non-diabetics (69 females and 87 males) aged 30–70 years (as control) was taken for lipid profile studies.ResultsLp(a) was significantly lower (p = 0.012) among T2DM subjects 0.123(1.12) g/L compared to non-diabetics 0.246 (1.18)g/L, irrespective of gender.A significant correlation (Spearman correlation, P = 0.047) was revealed between Lp(a) and IHD among Omani T2DM subjects. The proportions of T2DM subjects with IHD and an Lp(a) >0.3 g/L was higher compared to T2DM without IHD irrespective of gender, for women 42% vs. 27% and for men 17.5 vs. 8%, respectively.A significant negative correlation existed between Lp(a) and triglycerides (r = 0.41, P = 0.002) among T2DM subjects. In contrast, a significant positive correlation existed between Lp(a) and LDL-chol among the non-diabetic subjects.Women had significantly higher Lp(a) concentration compared to men ( 0.30 Vs. 0.16 g/L, P < 0.0001) irrespective of the diabetic status.ConclusionLp(a) is an independent risk factor for IHD among Omani T2DM subjects. Lp(a) concentration was significantly lower and negatively correlated with triglycerides among Omani diabetic compared to non-diabetic subjects.