Hakki Tastan

MEFV mutations in Turkish patients suffering from familial Mediterranean fever

Familial Mediterranean fever (FMF) is a recessive inherited disorder affecting Sephardic Jews, Arabs, Armenians and Turks. The gene responsible for FMF was recently cloned and several disease‐associated mutations have been described. We have evaluated seven MEFV mutations in 460 chromosomes of 230 unrelated patients with FMF living in Turkey, using PCR methods. The M694V allele accounted for 43.5% of the alleles studied and 19.1% of the patients were homozygous. The M680I, V726A and M694I mutations were responsible for 12.0%, 11.1% and 2.8% of the patients respectively. R761H, K695R and E148Q were rarely encountered. Two thirds of the disease alleles were attributed to three common mutations: M694V, M680V and V726A, but only 54% of the patients carried one or two of the three mutations. Adding the four rarer mutations increased these figures to 72% and 60%, respectively. Altogether, 79.6% of the patients bore at least one of the main mutations, and 84.3% carried at least one of the seven mutations studied. The 28 patients suffering also from amyloidosis carried at least one of five mutations, M694V being the most common. These results suggest that the origin of FMF in Turkey is heterogenous, all common mutations are associated with amyloidosis. Further, rapid and accurate molecular diagnosis of FMF is feasible in most cases. Hum Mutat 15:118–119, 2000.

Evidence for single origins of 35delG and delE120 mutations in the GJB2 gene in Anatolia.

Eighteen different sequence changes, including three novel alterations, were detected in GJB2, encoding connexin 26, in 371 Turkish probands with non‐syndromic sensorineural hearing loss. Two frequently detected mutations, 35delG and delE120, were shown to have single origins based on the conserved genotypes of two closely linked microsatellite and five single nucleotide polymorphism markers. Carrier frequencies of 35delG and delE120 in Egypt and Turkic populations of the Near East provide insights about the origin of these two mutations.

GJB2 Mutations in Mongolia: Complex Alleles, Low Frequency, and Reduced Fitness of the Deaf

We screened the GJB2 gene for mutations in 534 (108 multiplex and 426 simplex) probands with non‐syndromic sensorineural deafness, who were ascertained through the only residential school for the deaf in Mongolia, and in 217 hearing controls. Twenty different alleles, including four novel changes, were identified. Biallelic GJB2 mutations were found in 4.5% of the deaf probands (8.3% in multiplex, 3.5% in simplex). The most common mutations were c.IVS1 + 1G > A (c.‐3201G > A) and c.235delC with allele frequencies of 3.5% and 1.5%, respectively. The c.IVS1 + 1G > A mutation appears to have diverse origins based on associated multiple haplotypes. The p.V27I and p.E114G variants were frequently detected in both deaf probands and hearing controls. The p.E114G variant was always in cis with the p.V27I variant. Although in vitro experiments using Xenopus oocytes have suggested that p.[V27I;E114G] disturbs the gap junction function of Cx26, the equal distribution of this complex allele in both deaf probands and hearing controls makes it a less likely cause of profound congenital deafness. We found a lower frequency of assortative mating (37.5%) and decreased genetic fitness (62%) of the deaf in Mongolia as compared to the western populations, which provides an explanation for lower frequency of GJB2 deafness in Mongolia.

MEFV mutations in multiplex families with familial Mediterranean fever : is a particular genotype necessary for amyloidosis?

Familial Mediterranean fever (FMF) is an autosomal recessive disease. It is characterized by recurrent febrile episodes in association with peritonitis, pleuritis, and arthritis. Progressive systemic amyloidosis is the most important complication of FMF that inevitably leads to chronic renal failure. Recently, the gene for FMF, MEFV, has been cloned and four missense mutations have been described: M694V, M680I, V726A, and M694I. Initial studies have suggested that the presence of the M694V mutation carries a significant risk for the development of amyloidosis. In this study, we present seven families, in which at least two individuals have been diagnosed with FMF and at least one with amyloidosis. Among 18 individuals, in whom molecular testing was performed for the four aforementioned mutations, ten had amyloidosis. None of these ten individuals was found to be homozygous for the M694V mutation. In three families, there were two sibs with amyloidosis. None of the sib‐pairs with amyloidosis was found to have the same genotype. There were two or more sibs with the same genotype in four families. Only one sib from each family developed amyloidosis in these families. These results provide evidence that FMF patients without the M694V mutation are also at risk for the development of amyloidosis. Particular mutations themselves do not appear to be sufficient to explain the occurrence of amyloidosis in all cases with FMF.

Histopathological and Ultrastructural Examination of the Rat Conjunctiva after Exposure to Tobacco Smoke

Exposure to tobacco smoke can cause irritation of the conjunctiva. We conducted this study to identify the effect of tobacco on rat conjunctiva. Animals were divided into experimental and control groups and we exposed the experimental group to tobacco smoke. Control group rats inhaled only room air. Spectrophotometric analysis of the smoke-air mixture revealed that many toxic substances were present in this compound. We found very high levels of plasma thiocyanate after exposure to smoke in experimental group animals but no increase in the control group. So, this data indicates that these animals inhaled smoke effectively in our method. After 3 months conjunctivas were examined by light and electron microscopy. In the experimental group, conjunctivas were thinned, atrophied and microvillous projections and desmosomal connections were absent in comparison with the control conjunctivas. This pathologic change is very similar to conjunctival response to chronic irritants of any type.

Direct detection of Hb C (B6 Glu-Lys) by BseRI analysis

Hemoglobin C (B6 Glu‐Lys) can be identified by different techniques. Here we describe a restriction enzyme digestion protocol (BseRI GAGGAG N10) for direct detection of this variant.

The Frequencies of the Serum Amyloid A2 Alleles in Healthy (Turkish, Azerbaijani, and Kazakh) Populations

The Amyloid A1 (AA1) and A2 (AA2) proteins, which result from proteolytic cleavage of the Serum Amyloid A1 (SAA1) and A2 (SAA2) proteins, are major protein components of the Amyloid A deposits found in secondary amyloidosis. This study determines frequency of serum amyloid A2 alleles (α, β) in healthy Turkish, Azerbaijani, and Kazakh subjects. Two hundred Turkish, sixty-five Azerbaijani and sixty-five Kazakh healthy individuals were studied by previously described the PCR-RFLP methods. Our data revealed that the frequencies of the α and β alleles at the SAA2 locus in the Turkish healthy population were different when compared to those in Azerbaijani and Kazakh healthy populations (P = 0.014 and 0.02), respectively. In contrast, the difference between α and β alleles at the SAA2 locus was not different in both Kazakh and Azerbaijani healthy populations (P = 0.882).

Erratum: Evidence for single origins of 35delG and delE120 mutations in the GJB2 gene in Anatolia (Clinical Genetics (2005) vol. 67 (31-37))

1)Wu BL, Lindeman N, Lip V, Adams A, Amato RS, Cox G, Irons M, Kenna M, Korf B, Raisen J, Platt O. Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing. Genet Med. 2002: 4: 279-88. Clin Genet 2005: 67: 273 Copyright # Blackwell Munksgaard 2005 Printed in Singapore. All rights reserved CLINICAL GENETICS doi: 10.1111/j.1399-0004.2005.00422.x