Transglutaminase-1 mutations in Omani families with lamellar ichthyosis.

OBJECTIVE: To determine the molecular basis of familial ichthyosis in three Omani families. SUBJECTS AND METHODS: Nine patients from three consanguineous families, A, B, and C, were born with typical features of lamellar ichthyosis subtype including collodion membrane and maintained ectropion, and epidermal scaling through their childhood. The 4 patients from family B had more severe symptoms requiring neonatal critical care and subsequent regular treatment with emollients, eye lubricants, and low-dose acitretin. DNA was extracted from peripheral blood by standard methods. The samples were initially genotyped to screen known loci linked to recessive ichthyosis on chromosomes 2q33-32 (ABCA12), 14q11 (TGM1), and 19p12-q12 using commercially supplied polymorphic fluorescent microsatellite markers. TGM1 was analyzed by direct sequencing for disease-associated mutations. RESULTS: Two known pathogenic mutations in TGM1 were detected: p.Gly278Arg in families A and B and p.Arg396His in family C. These two mutations were segregating in an autosomal recessive mode of inheritance. CONCLUSION: Two known pathogenic TGM1 mutations were detected in three large consanguineous Omani families with lamellar ichthyosis. This study confirmed the geographic distribution of known mutations to an apparently unrelated population.

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.

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 ß 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 E polymorphism in Omani dyslipidemic patients with and without coronary artery disease.

Apolipoprotein E (APOE) polymorphism is a predictor of interindividual variability in plasma levels of lipids and lipoproteins and a predictor of risk of coronary artery disease (CAD). We studied the relationship between APOE polymorphism and lipid profiles and risk of CAD in Omani dyslipidemic patients. This retrospective study included 244 dyslipidemic patients, of whom 67 had CAD. Fasting blood glucose, lipids, and plasma lipoprotein levels were measured using standard methods, and APOE genotypes were detected by PCR-RFLP. The dyslipidemic patients had the following APOE allele frequencies: APOE*2, 0.030; APOE*3, 0.894; and APOE*4, 0.076. APOE allele frequencies between patients with and without CAD showed no significant differences. Compared to APOE*3/*3 homozygotes, APOE*4 allele patients had higher mean levels of low-density lipoprotein (LDL) cholesterol (p = 0.014), apoB (p = 0.031), lower mean levels of apoA1 (p = 0.043), and a trend of higher mean level of total cholesterol (p = 0.084). Thirty-one percent of patients with CAD had the APOE*4 allele compared to 26% with the APOE*3 allele, but this difference was not significant. Compared with APOE*3/*3 homozygotes, patients with the APOE*4 allele had 1.3 times higher risk for CAD after ignoring dyslipidemia, but this risk was modified after adjusting for dyslipidemia. In conclusion, among dyslipidemic patients, carriers of APOE*4 compared to homozygous carriers of APOE*3 had significantly higher levels of LDL cholesterol and apoB, but no relationship with CAD was found.

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: epsilon2, 0.052; epsilon3, 0.886; epsilon4, 0.062. This pattern of distribution, characterized by the lowest epsilon4 and among the highest epsilon3 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 epsilon4 and high epsilon3 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.

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.

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.