Gamze Guven

Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

A novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family

Triggering receptor expressed on myeloid cells 2 (TREM2) homozygous mutations cause Nasu-Hakola disease, an early-onset recessive form of dementia preceded by bone cysts and fractures. The same type of mutations has recently been shown to cause frontotemporal dementia (FTD) without the presence of any bone phenotype. Here, we further confirm the association of TREM2 mutations with FTD-like phenotypes by reporting the first compound heterozygous mutation in a Turkish family.

A new F‐box protein 7 gene mutation causing typical Parkinson's disease

Recessive mutations in the F‐box protein 7 gene (FBXO7; PARK15) have been identified as a cause of the parkinsonian‐pyramidal syndrome. Here, we report clinical and genetic findings in a Turkish family with novel FBXO7 mutations.

A novel A781V mutation in the CSF1R gene causes hereditary diffuse leucoencephalopathy with axonal spheroids

We report a family with a novel CSF1R mutation causing hereditary diffuse leucoencephalopathy with axonal spheroids. Family members presented with neuropsychiatric and behavioural symptoms, with subsequent development of motor symptoms and gait disturbance. MRI brain showed extensive white matter change with a frontal predominance and associated atrophy in two members of the family. Genetic testing revealed a novel mutation c.2342C > T (p.A781V) in the CSF1R gene in two brothers of the family. This report highlights the difficulties in diagnosing HDLS and discusses the indications for testing for mutations in the CSF1R gene.

A novel homozygous DJ1 mutation causes parkinsonism and ALS in a Turkish family

OBJECTIVE DJ1 mutations (PARK7) are among the monogenic causes of early-onset autosomal recessive parkinsonism. Here, we report clinical and genetic findings in a family with Turkish origin carrying a new DJ1 mutation and presenting with early-onset levodopa responsive parkinsonism and signs of amyotrophic lateral sclerosis (ALS). METHODS The family consisted of 12 members including 10 offsprings of whom three were affected. All family members underwent detailed clinical examination. DNA samples from the index case, his unaffected sister, and his parents were subjected to whole genome sequencing analysis. RESULTS The index case 38-year-old man developed left hand tremor at the age of 24 years. He had progressive asymmetrical parkinsonism, depression and developed signs of ALS within 4 years. His two affected sisters had young-onset asymmetrical tremor-dominant parkinsonism with signs of ALS. A new homozygous p.Q45X mutation in exon 3 in DJ1 was found in all three patients. Their unaffected parents and one clinically healthy sibling were found to be heterozygous for this mutation. CONCLUSIONS This is the second report of DJ1 mutations associated with parkinsonism and ALS. This is relevant for genetic counseling as well as for understanding the pathogenesis of the broad spectrum of parkinsonism-ALS disease complex.

Mutation Frequency of the Major Frontotemporal Dementia Genes, MAPT, GRN and C9ORF72 in a Turkish Cohort of Dementia Patients.

‘Microtubule-associated protein tau’ (MAPT), ‘granulin’ (GRN) and ‘chromosome 9 open reading frame72’ (C9ORF72) gene mutations are the major known genetic causes of frontotemporal dementia (FTD). Recent studies suggest that mutations in these genes may also be associated with other forms of dementia. Therefore we investigated whether MAPT, GRN and C9ORF72 gene mutations are major contributors to dementia in a random, unselected Turkish cohort of dementia patients. A combination of whole-exome sequencing, Sanger sequencing and fragment analysis/Southern blot was performed in order to identify pathogenic mutations and novel variants in these genes as well as other FTD-related genes such as the ‘charged multivesicular body protein 2B’ (CHMP2B), the ‘FUS RNA binding protein’ (FUS), the ‘TAR DNA binding protein’ (TARDBP), the ‘sequestosome1’ (SQSTM1), and the ‘valosin containing protein’ (VCP). We determined one pathogenic MAPT mutation (c.1906C>T, p.P636L) and one novel missense variant (c.38A>G, p.D13G). In GRN we identified a probably pathogenic TGAG deletion in the splice donor site of exon 6. Three patients were found to carry the GGGGCC expansions in the non-coding region of the C9ORF72 gene. In summary, a complete screening for mutations in MAPT, GRN and C9ORF72 genes revealed a frequency of 5.4% of pathogenic mutations in a random cohort of 93 Turkish index patients with dementia.

Clinical variability in ataxia-telangiectasia.

Ataxia–telangiectasia (A-T) is an autosomal recessive inherited disease characterized by progressive childhood-onset cerebellar ataxia, oculomotor apraxia, choreoathetosis and telangiectasias of the conjunctivae. Further symptoms may be immunodeficiency and frequent infections, and an increased risk of malignancy. As well as this classic manifestation, several other non-classic forms exist, including milder or incomplete A-T phenotypes caused by homozygous or compound heterozygous mutations in the ATM gene. Recently, ATM mutations have been found in 13 Canadian Mennonites with early-onset, isolated, predominantly cervical dystonia, in a French family with generalized dystonia and in an Indian family with dopa-responsive cervical dystonia. In this article, we will describe a Turkish family with three affected sibs. Their phenotypes range from pure cervical dystonia associated with hand tremor to truncal and more generalized dystonic postures. Exome sequencing has revealed the potentially pathogenic compound heterozygous variants p.V2716A and p.G301VfsX19 in the ATM gene. The variants segregated perfectly with the phenotypes within the family. Both mutations detected in ATM have been shown to be pathogenic, and the α-fetoprotein, a marker of ataxia telangiectasia, was found to be increased. This report supports recent literature showing that ATM mutations are not exclusively associated with A-T but may also cause a more, even intra-familial variable phenotype in particular in association with dystonia.

Mutations in TYROBP are not a common cause of dementia in a Turkish cohort

Mutations in TYROBP and TREM2 have been shown to cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy. Recently, variants in TREM2 were also associated with frontotemporal dementia and Alzheimers disease. Given the functional proximity between these 2 genes, we investigated the genetic variation of TYROBP in a Turkish cohort of 103 dementia patients. No mutations or copy number variants predicted to be pathogenic were identified. These results indicate that mutations in TYROBP are not a common cause of dementia in this Turkish cohort.

PLA2G6 Mutations Related to Distinct Phenotypes: A New Case with Early-onset Parkinsonism

Background PLA2G6-associated neurodegeneration (PLAN) is a recessive neurodegenerative disorder characterized by three distinct phenotypes: infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (atypical NAD), and PLA2G6-related dystonia–parkinsonism. Methods A consanguineous index case from Turkey was diagnosed with early-onset Parkinsonism at the Istanbul Faculty of Medicine. She and her unaffected brother were subjected to whole-genome sequencing. Results In this report, we describe a 33-year-old index case with parental consanguinity and early-onset Parkinsonism. Whole-genome sequencing of this individual revealed that a homozygous p.R747W mutation in PLA2G6 segregates with the disease in this family Discussion This result supports the importance of prioritizing this gene in mutational analysis of autosomal recessive Parkinsonism, and confirms the clinical heterogeneity of PLAN.

A novel homozygous COL11A2 deletion causes a C-terminal protein truncation with incomplete mRNA decay in a Turkish patient†

Recessive mutations in COL11A2 (collagen, type XI, alpha 2), are responsible for otospondylomegaepiphyseal dysplasia (OSMED) and non‐syndromic hearing loss while dominant mutations are associated with Stickler type III, isolated cleft palate, Robin sequence, non‐ophthalmic Stickler syndrome, early onset osteoarthritis and autosomal dominant hearing loss. We describe here the clinical findings of two Turkish cousins with OSMED carrying a novel homozygous truncating mutation in exon 38 of COL11A2 gene, c.2763delT, identified on cDNA and confirmed at gDNA. This mutation is located on triple helix repeat domain of the collagen alpha‐2(XI) chain, where the majority of the previously identified mutations are located. Real‐time RT‐PCR experiment provided that mutated transcript does not decay completely. Although our analysis displays the partial survival of the mutant transcript from blood tissue, not from cartilage, we propose that this mechanism may play an important role on the variable expressivity of the heterozygous COL11A2 gene mutations.