Rıza Köksal Özgül

Private SACS mutations in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) families from Turkey.

Abstract.We studied five families with pediatric-onset recessive spastic ataxia from Turkey. The clinical characteristics and linkage studies are compatible with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). SACS mutations are responsible for ARSACS in Québec families. In four of the five families tested we detected new disease-causing mutations using automated sequencing of SACS. Our study raises to 12 the number of SACS mutations detected in ARSACS patients with origins around the Mediterranean basin.

Identification of a Novel Twinkle Mutation in a Family With Infantile Onset Spinocerebellar Ataxia by Whole Exome Sequencing

Whole exome sequencing combined with homozygosity mapping comprises a genetic diagnostic tool to identify genetic defects in families with multiple affected members, compatible with presumed autosomal recessively inherited neurometabolic/neurogenetic disease. These tools were applied to a family with two individuals manifesting ataxia, associated with peripheral sensory neuropathy, athetosis, seizures, deafness, and ophthalmoplegia. A novel homozygous missense mutation c.1366C>G (L456V) in C10orf2 (the Twinkle gene) was identified, confirming infantile onset spinocerebellar ataxia in the probands. Signs in infantile onset spinocerebellar ataxia follow a fairly distinct pattern, affecting early development, followed by ataxia and loss of skills. However, this very rare disease was previously reported only in Finland. We suggest that infantile onset spinocerebellar ataxia should be more frequently considered in the differential diagnosis of neurometabolic diseases in childhood. Next-generation sequencing and its use along with homozygosity mapping offer highly promising techniques for molecular diagnosis, especially in small families affected with very rare neurometabolic disorders such as infantile onset spinocerebellar ataxia.

The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey.

Correction to: Journal of Human Genetics (2015) 60, 1–9; doi:10.1038/jhg.2014.85; published online 9 October 2014 Since the advance online publication of this article, the authors of the above paper have noticed errors in the list of authors and affiliations. Article with correct authors informationnow appears in this issue.

Molecular analysis and long-term clinical evaluation of three siblings with Alström syndrome.

Alström syndrome is a rare, autosomal recessive disorder characterized by a wide spectrum of clinical features including early‐onset retinal degeneration leading to blindness, sensorineural hearing loss, short stature, obesity, type 2 diabetes, hyperlipidemia and dilated cardiomyopathy. Renal, hepatic and pulmonary dysfunction may occur in the later phases of the disease. The three affected sisters, from a consanguineous Turkish family, with the characteristic features of Alström syndrome, were clinically diagnosed in 1987 and followed for 20 years. DNA sequence analysis of ALMS1, the causative gene in Alström syndrome, identified a novel homozygous disease‐causing mutation, c.8164C>T, resulting in a premature termination codon in exon 10 in each of the three affected sisters. Furthermore, we describe the longitudinal disease progression in this family and report new clinical findings likely associated with Alström syndrome, such as pes planus and hyperthyroidism.

Homozygous GNAL mutation associated with familial childhood-onset generalized dystonia

Heterozygous loss-of-function mutations in the GNAL gene encoding the α subunit of the heterotrimeric G protein Golf (Gαolf) are known to cause isolated dystonia.1,2 Gαolf is enriched in the striatum where it couples D1 dopamine (D1R) and A2A adenosine (A2AR) receptors to the activation of adenylyl cyclase type 5 (AC5). Mutations in ADCY5, the gene encoding AC5, are also known to lead to chorea and dystonia.3,4 Previous functional studies of mutated Gαolf variants have revealed deficiencies in activation after D1R stimulation.1,5

Association of CFH Y402H Polymorphism with Both Forms of Advanced Age-Related Macular Degeneration in Turkish Patients

Purpose: The purpose of this study was to investigate the association between complement factor H Y402H polymorphism and age-related macular degeneration (AMD) development in a cohort of Turkish patients. Methods: A total of 182 individuals, including 95 individuals with unrelated late age-related macular degeneration and 87 age-matched healthy individuals as a control group were genotyped with polymerase chain reaction followed by restriction enzyme digestion and direct sequence analysis. The statistical analysis was performed with statistical software R 2.9.2 and epicalc package. Results: The Y402H variant in the CFH gene was found to be associated with late AMD in our study population. Genotypic frequencies were highly different between all patients and control individuals compared for the heterozygotes carrying the risk allele C (AMD patients (CT) 70.5%, control individuals (CT) 54.02%; χ2= 5.285, d.f. = 1, p = 0.02). When all AMD patients were compared with the healthy control group, TC heterozygotes showed a significantly increased risk of AMD (O.R = 2.32, CI% 1.23–4.35). Conclusıon: This study suggests that the CFH Y402H polymorphism is associated with increased risk for both types of end-stage AMD in Turkish patients.

Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

Primary systemic carnitine deficiency (SCD) is an autosomal recessive disorder caused by defective cellular carnitine transport. Patients usually present with predominant metabolic or cardiac manifestations. SCD is caused by mutations in the organic cation/carnitine transporter OCTN2 (SLC22A5) gene. Mutation analysis of SLC22A5 gene was carried out in eight Turkish patients from six families. Six patients presented with signs and symptoms of heart failure, cardiomyopathy, and low plasma carnitine levels, five of them with concurrent anemia. A patient with dilated cardiomyopathy had also facial dysmorphia, microcephaly, and developmental delay. Tandem MS analyses in siblings of the patients revealed two more cases with low plasma carnitine levels. SCD diagnosis was confirmed in these two cases by mutation screening. These two cases were asymptomatic but echocardiography revealed left ventricular dilatation in one of them. Carnitine treatment was started before the systemic signs and symptoms developed in these patients. Mean value of serum carnitine levels of the patients was 2.63±1.92μmol/L at the time of diagnosis. After 1year of treatment, carnitine values increased to 16.62±5.11 (p<0.001) and all responded to carnitine supplementation clinically. Mutation screening of the OCTN2 gene study in the patients revealed two novel (p.G411V, p.G152R), and four previously identified mutations (p.R254X, p.R282X, p.R289X, p.T337Pfs12X). Early recognition and carnitine supplementation can be lifesaving in this inborn error of fatty acid oxidation.

Retinitis pigmentosa caused by mutations in the ciliary MAK gene is relatively mild and is not associated with apparent extra-ocular features.

Defects in MAK, encoding a protein localized to the photoreceptor connecting cilium, have recently been associated with autosomal recessive retinitis pigmentosa (RP). The aim of this study is to describe our detailed clinical observations in patients with MAK‐associated RP, including an assessment of syndromic symptoms frequently observed in ciliopathies.

Phenotypic and genotypic spectrum of Turkish patients with isovaleric acidemia.

We aim to investigate the genetic basis of isovaleryl-CoA dehydrogenase (IVD) gene mutations and genotype-phenotype correlations in Turkish patients. Accordingly, bi-directional sequencing was performed to screen 26 patients with isovaleric acidemia (IVA). Nine novels (c.145delC, c.234 + 3G > C, c.506_507insT, p.Glu85Gln, p.Met147Val, p.Ala268Val, p.Ile287Met, p.Gly346Asp and p.Arg382Trp) and six previously reported (c.456 + 2T > C, p.Arg21His, p.Arg21Pro, p.Arg363Cys, p.Arg363His p.Glu379Lys) pathogenic mutations were identified. Pathogenicity of the novel mutations was supported using computational programs. No clear genotype-phenotype correlation could be determined. One of the cases with the novel c.234 + 3G > C mutation has portoseptal liver fibrosis, the clinical condition that was first reported for IVA. This study is the first comprehensive report from Turkey related to IVA genetics that provides information about the high number of disease-causing novel mutations.

Dynamics of the rhomboid-like protein RHBDD2 expression in mouse retina and involvement of its human ortholog in retinitis pigmentosa.

Background: RHBDD2 is distantly related to rhomboids, membrane-bound proteases. Results: In retina, RHBDD2 exists as a monomer in all cells throughout life and a homotrimer only in cone outer segments; a mutation in RHBDD2 possibly leads to retinitis pigmentosa. Conclusion: RHBDD2 plays important roles in development and normal retinal function. Significance: This is the first characterization of RHBDD2 and its association with retinal disease. The novel rhomboid-like protein RHBDD2 is distantly related to rhomboid proteins, a group of highly specialized membrane-bound proteases that catalyze regulated intramembrane proteolysis. In retina, RHBDD2 is expressed from embryonic stages to adulthood, and its levels show age-dependent changes. RHBDD2 is distinctly abundant in the perinuclear region of cells, and it localizes to their Golgi. A glycine zipper motif present in one of the transmembrane domains of RHBDD2 is important for its packing into the Golgi membranes. Its deletion causes dislodgment of RHBDD2 from the Golgi. A specific antibody against RHBDD2 recognizes two forms of the protein, one with low (39 kDa; RHBDD2L) and the other with high (117 kDa; RHBDD2H) molecular masses in mouse retinal extracts. RHBDD2L seems to be ubiquitously expressed in all retinal cells. In contrast, RHBDD2H seems to be present only in the outer segments of cone photoreceptors and may correspond to a homotrimer of RHBDD2L. This protein consistently co-localizes with S- and M-types of cone opsins. We identified a homozygous mutation in the human RHBDD2 gene, R85H, that co-segregates with disease in affected members of a family with autosomal recessive retinitis pigmentosa. Our findings suggest that the RHBDD2 protein plays important roles in the development and normal function of the retina.