FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing.

In a large consanguineous Turkish kindred with recessive nonsyndromic, prelingual, profound hearing loss, we identified in the gene FAM65B (MIM611410) a splice site mutation (c.102-1G>A) that perfectly cosegregates with the phenotype in the family. The mutation leads to exon skipping and deletion of 52-amino acid residues of a PX membrane localization domain. FAM65B is known to be involved in myotube formation and in regulation of cell adhesion, polarization, and migration. We show that wild-type Fam65b is expressed during embryonic and postnatal development stages in murine cochlea, and that the protein localizes to the plasma membranes of the stereocilia of inner and outer hair cells of the inner ear. The wild-type protein targets the plasma membrane, whereas the mutant protein accumulates in cytoplasmic inclusion bodies and does not reach the membrane. In zebrafish, knockdown of fam65b leads to significant reduction of numbers of saccular hair cells and neuromasts and to hearing loss. We conclude that FAM65B is a plasma membrane-associated protein of hair cell stereocilia that is essential for hearing.

ATP6V1B1 mutations in distal renal tubular acidosis and sensorineural hearing loss: clinical and genetic spectrum of five families.

Distal renal tubular acidosis (DRTA) is characterized by tubular defects in urinary acidification and hyperchloremic metabolic acidosis, hypokalemia, hypercalciuria, hypocitraturia, nephrocalcinosis and nephrolithiasis. Mutations in ATP6V1B1 cause DRTA associated with sensorineural hearing loss. The objective of this multicenter study is to screen DRTA patients with sensorineural hearing loss for ATP6V1B1 gene mutations and present genotype/phenotype correlation. Clinical data in five unrelated consanguineous families with DRTA and hearing loss were obtained in Turkey. For mutation screening, all coding exons of ATP6V1B1 were PCR-amplified and sequenced from genomic DNA. In our cohort of five families, there were four different homozygous ATP6V1B1 mutations in affected individuals: c.91C>T (p.R31X), c.232G>A (p.G78R), c.497delC (p.T166RfsX9) and c.1155dupC (p.I386HfsX56). Our study shows that rare and family-specific variants in ATP6V1B1 are responsible for DRTA and sensorineural hearing loss syndrome in Turkey. While firm genotype-phenotype correlations are not available, detailed clinical and molecular analyses provide data to be used in genetic counseling.

A novel COL4A3 mutation causes autosomal-recessive Alport syndrome in a large Turkish family.

BACKGROUND: Alport syndrome (AS) is a genetically heterogeneous disorder that is characterized by hematuria, progressive renal failure typically resulting in end-stage renal disease, sensorineural hearing loss, and variable ocular abnormalities. Only 15% of cases with AS are autosomal recessive and are caused by mutations in the COL4A3 or COL4A4 genes, encoding type IV collagen. METHODS: Clinical data in a large consanguineous family with four affected members were reviewed, and genomic DNA was extracted. For mapping, 15 microsatellite markers flanking COL4A3, COL4A4, and COL4A5 in 16 family members were typed. For mutation screening, all coding exons of COL4A3 were polymerase chain reaction- amplified and Sanger-sequenced from genomic DNA. RESULTS: The disease locus was mapped to chromosome 2q36.3, where COL4A3 and COL4A4 reside. Sanger sequencing revealed a novel mis-sense mutation (c.2T>C; p.M1T) in exon 1 of COL4A3. The identified nucleotide change was not found in 100 healthy ethnicity-matched controls via Sanger sequencing. CONCLUSIONS: We present a large consanguineous Turkish family with AS that was found to have a COL4A3 mutation as the cause of the disease. Although the relationship between the various genotypes and phenotypes in AS has not been fully elucidated, detailed clinical and molecular analyses are helpful for providing data to be used in genetic counseling. It is important to identify new mutations to clarify their clinical importance, to assess the prognosis of the disease, and to avoid renal biopsy for final diagnosis.

A novel homozygous GALC mutation: very early onset and rapidly progressive Krabbe disease.

A clear cut genotype-phenotype correlation for Krabbe disease is not available. Therefore, it is important to identify new mutations and their associated phenotypes to predict the prognosis of the disease. The aim of this study is to identify the causative mutation(s) in a family with Krabbe disease. After a clinical evaluation and suspicion of Krabbe disease galactocerebrosidase activity was analyzed and GALC gene mutation analysis was performed. The galactocerebrosidase enzyme activity was 0.01 nmol/mg/h protein (normal range 0.8-4). For further investigation mutation screening was performed by Sanger sequencing across the 17 exons of GALC gene. A novel homozygous mutation c.727delT (p.S243QfsX7) was found. In this study we present the clinical findings along with a novel GALC mutation in a consanguineous Turkish family. Although the relationship between the various genotypes and phenotypes in Krabbe disease has not been fully elucidated an accurate genetic family study is helpful for genetic counseling follow-up and therapy of Krabbe disease. Also, it is important to identify new mutations in order to clarify their clinical importance, to assess the prognosis of the disease, and to suggest either prenatal diagnosis or preimplantation genetic diagnosis to the effected families.

Novel mutations of ABCA1 transporter in patients with Tangier disease and familial HDL deficiency.

The objective of the study was the characterization of ABCA1 gene mutations in 10 patients with extremely low HDL-cholesterol. Five patients (aged 6 months to 76 years) presented with splenomegaly and thrombocytopenia suggesting the diagnosis of Tangier disease (TD). Three of them were homozygous for novel mutations either in intron (c.4465-34A>G) or in exons (c.4376delT and c.5449C>T), predicted to encode truncated proteins. One patient was compound heterozygous for a nucleotide insertion (c.1758_1759insG), resulting in a truncated protein and for a nucleotide substitution c.4799A>G, resulting in a missense mutation (p.H1600R). The last TD patient, found to be heterozygous for a known mutation (p.D1009Y), had a complete defect in ABCA1-mediated cholesterol efflux in fibroblasts, suggesting the presence of a second undetected mutant allele. Among the other patients, four were asymptomatic, but one, with multiple risk factors, had severe peripheral artery disease. Three of these patients were heterozygous for known mutations (p.R130K+p.N1800H, p.R1068C, p.N1800H), while two were carriers of novel mutations (c.1195-27G>A and c.396_397insA), predicted to encode truncated proteins. The pathogenic effect of the two intronic mutations (c. 1195-27G>A and c.4465-34A>G) was demonstrated by the analysis of the transcripts of splicing reporter mutant minigenes expressed in COS-1 cells. Both mutations activated an intronic acceptor splice site which resulted in a partial intron retention in mature mRNA with the production of truncated proteins. This study confirms the allelic heterogeneity of TD and suggests that the diagnosis of TD must be considered in patients with an unexplained splenomegaly, associated with thrombocytopenia and hypocholesterolemia.

Inherited mutation of the luteinizing hormone/choriogonadotropin receptor (LHCGR) in empty follicle syndrome.

OBJECTIVE: To test by genomic analysis whether empty follicle syndrome (EFS) in a family with two affected sisters has a genetic basis. DESIGN: Whole-exome sequencing in the context of clinical genetics. SETTING: University hospital. PATIENT(S): Two women (36 and 32 years old at the time of the study) with EFS. INTERVENTION(S): Genetic counseling based on autosomal recessive inheritance. MAIN OUTCOME MEASURE(S): Discovery of a mutation in the LH/choriogonadotropin receptor (LHCGR) as the cause of EFS. RESULT(S): A novel missense mutation in LHCGR, p.N400S, was homozygous in sisters with EFS and/or infertility, but not in their unaffected siblings or parents. The mutation was not present in 500 ancestry-matched control subjects. Asparagine at residue 400 is highly conserved and its substitution by serine predicted to alter critical interactions that stabilize LHCGR. CONCLUSION(S): We describe a genetic basis for EFS and provide strong evidence for the existence of genuine EFS in some patients. A mutation impairing the function of LHCGR explains the lack of response of these patients to repeated administration of ß-hCG.

Prediction, prevention and personalisation of medication for the prenatal period: genetic prenatal tests for both rare and common diseases.

Genetic testing usually helps physicians to determine possible genetic diseases in unborn babies, genetic disorders of patients and the carriers who might pass the mutant gene on to their children. They are performed on blood, tissues or other body fluids. In recent years, the screening tests and diagnostic tests have improved quickly and, as a result, the risks of pregnancy can be determined more commonly and physicians can diagnose several genetic disorders in the prenatal period. Detecting the abnormalities in utero enables correct management of the pregnancy, prenatal and postnatal medical care, and it is also important for making well informed decisions about continuing or terminating a pregnancy. Besides the improvements of conventional invasive diagnostic tests, the discovery of circulating cell-free foetal nucleic acids in maternal plasma has developed a new point of view for non-invasive prenatal diagnosis recently.

Healthcare in overview of Turkey.

Turkey is one of the leading countries with its developing economy, high young population, and with its geopolitical location being an intersection between Asia and Europe. It is aimed at setting a good example for developed and developing countries with its health policy targets. We reported and discussed here the demographic data of Turkish population, the main aims of Ministry of Health, social security system and its scope and structure, health services, healthcare institutions and their infrastructures, human resources in health, health staff training and also outline of Turkish foreign policy. We mentioned predictive, preventive, personalized and participatory medicine according to Turkey's healthcare approach.