Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the Ad... more Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the Additional Supporting Information may be found in the online version of this article.
Cerebellar ataxia, mental retardation and dysequilibrium syndrome is a rare and heterogeneous con... more Cerebellar ataxia, mental retardation and dysequilibrium syndrome is a rare and heterogeneous condition. We investigated a consanguineous family from Turkey with four affected individuals exhibiting the condition. Homozygosity mapping revealed that several shared homozygous regions, including chromosome 13q12. Targeted next-generation sequencing of an affected individual followed by segregation analysis, population screening and prediction approaches revealed a novel missense variant, p.I376M, in ATP8A2. The mutation lies in a highly conserved C-terminal transmembrane region of E1 E2 ATPase domain. The ATP8A2 gene is mainly expressed in brain and development, in particular cerebellum. Interestingly, an unrelated individual has been identified, in whom mental retardation and severe hypotonia is associated with a de novo t(10;13) balanced translocation resulting with the disruption of ATP8A2. These findings suggest that ATP8A2 is involved in the development of the cerebrocerebellar structures required for posture and gait in humans.
preceding neuron loss within the thalamocortical system by several months. These effects extend b... more preceding neuron loss within the thalamocortical system by several months. These effects extend beyond sensory relay nuclei of the thalamus with subsets of GFAP-positive astrocytes also staining intensely for glutamate, raising the possibility of localized excitotoxicity during NCL pathogenesis. We have also found evidence for presynaptic reorganization in thalamocortical neurons of NCL mouse models, with altered SNAP/ SNARE complex formation, synaptic vesicle density and docking. It appears that these synaptic events also precede the onset of neuron loss. Indeed, immunohistochemical and ultrastructural evidence suggests that some of these presynaptic effects might be mediated by astrocytes. Taken together these data suggest that the presynaptic compartment is a key target in NCL pathogenesis.
Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary... more Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology. CMT4C is inherited as an autosomal recessive trait and has been mapped to a 13-cM linkage interval on chromosome 5q23-q33. By homozygosity mapping and allele-sharing analysis, we refined the CMT4C locus to a suggestive critical region of 1.7 Mb. We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy. We observed eight distinct protein-truncating mutations and three nonconservative missense mutations affecting amino acids conserved through evolution. In all families, we identified a mutation on each disease allele, either in the homozygous or in the compound heterozygous state. The CMT4C gene is strongly expressed in neural tissues, including peripheral nerve tissue. The translated protein defines a new protein family of unknown function with putative orthologues in vertebrates. Comparative sequence alignments indicate that members of this protein family contain multiple SH3 and TPR domains that are likely involved in the formation of protein complexes.
Mutations in the myotubularin-related protein 2 gene on chromosome 11q22 are known to cause autos... more Mutations in the myotubularin-related protein 2 gene on chromosome 11q22 are known to cause autosomal recessive Charcot–Marie–Tooth disease with irregularly folded myelin sheaths. We screened the coding region of the myotubularin-related protein 2 gene in a Turkish consanguineous Charcot–Marie–Tooth disease family compatible with linkage to chromosome 11q22. A homozygous cytosine to thymine missense mutation at nucleotide position 847, resulting in
Congenital muscular dystrophies (CMDs) are a genetically and clinically heterogeneous group of ne... more Congenital muscular dystrophies (CMDs) are a genetically and clinically heterogeneous group of neuromuscular disorders. Several genes encoding extracellular matrix, nuclear envelope, sarcolemmal proteins and glycosylation enzymes have been implicated in CMDs. The large overlap of clinical presentations due to mutations in different genes poses a challenge for clinicians in determining disease etiology for each patient. We investigated the use of whole exome sequencing (WES) in identifying the genetic cause of disease in 5 CMD patients from 3 families who presented with highly similar clinical features, including early-onset rapidly progressive weakness without brain or eye abnormalities. Whole exome sequencing was performed on DNA from affected individuals. Potential functional impacts of mutations were investigated by immunostaining on available muscle biopsies. Pathogenic mutations in 3 different genes, DYSF, FKTN, and ISPD were identified in each family. Mutation in DYSF led to a...
Limb-girdle muscular dystrophies constitute a broad range of clinical and genetic entities. We ha... more Limb-girdle muscular dystrophies constitute a broad range of clinical and genetic entities. We have evaluated 38 autosomal recessive limb-girdle muscular dystrophy (LGMD2) families by linkage analysis for the known loci of LGMD2A-F and protein studies using immunofluorescence and western blotting of the sarcoglycan complex. One index case in each family was investigated thoroughly. The age of onset and the current
Cardiomyopathy (CMP) in childhood is an etiologically heterogeneous group of cardiac disease, inc... more Cardiomyopathy (CMP) in childhood is an etiologically heterogeneous group of cardiac disease, including many genetic, metabolic, neuromuscular and environmental causes. The goal of this study is to determine the underlying causes and clinical characteristics of children presenting with CMP to a tertiary medical center in Turkey. We analyzed the data of 109 patients retrospectively, who presented with CMP as an initial feature, and without a specific diagnosis, between May 2007 and May 2012. Patients who already developed CMP during the course of a diagnosed disease were excluded from the study. Among 109 patients, 57 were male, and 52 were female. Most of the patients were symptomatic (n = 59) in the first year of life (54.1%). The patients were subdivided into three groups, as dilated CMP (n = 69, 63.3%), hypertrophic CMP (n = 32, 9.4%), and restrictive CMP (n = 8, 7.3%). The etiology remained unknown in 68.8% of all cases. Inborn errors of metabolism (n = 16) and cardiac diseases ...
Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the Ad... more Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the Additional Supporting Information may be found in the online version of this article.
Cerebellar ataxia, mental retardation and dysequilibrium syndrome is a rare and heterogeneous con... more Cerebellar ataxia, mental retardation and dysequilibrium syndrome is a rare and heterogeneous condition. We investigated a consanguineous family from Turkey with four affected individuals exhibiting the condition. Homozygosity mapping revealed that several shared homozygous regions, including chromosome 13q12. Targeted next-generation sequencing of an affected individual followed by segregation analysis, population screening and prediction approaches revealed a novel missense variant, p.I376M, in ATP8A2. The mutation lies in a highly conserved C-terminal transmembrane region of E1 E2 ATPase domain. The ATP8A2 gene is mainly expressed in brain and development, in particular cerebellum. Interestingly, an unrelated individual has been identified, in whom mental retardation and severe hypotonia is associated with a de novo t(10;13) balanced translocation resulting with the disruption of ATP8A2. These findings suggest that ATP8A2 is involved in the development of the cerebrocerebellar structures required for posture and gait in humans.
preceding neuron loss within the thalamocortical system by several months. These effects extend b... more preceding neuron loss within the thalamocortical system by several months. These effects extend beyond sensory relay nuclei of the thalamus with subsets of GFAP-positive astrocytes also staining intensely for glutamate, raising the possibility of localized excitotoxicity during NCL pathogenesis. We have also found evidence for presynaptic reorganization in thalamocortical neurons of NCL mouse models, with altered SNAP/ SNARE complex formation, synaptic vesicle density and docking. It appears that these synaptic events also precede the onset of neuron loss. Indeed, immunohistochemical and ultrastructural evidence suggests that some of these presynaptic effects might be mediated by astrocytes. Taken together these data suggest that the presynaptic compartment is a key target in NCL pathogenesis.
Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary... more Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology. CMT4C is inherited as an autosomal recessive trait and has been mapped to a 13-cM linkage interval on chromosome 5q23-q33. By homozygosity mapping and allele-sharing analysis, we refined the CMT4C locus to a suggestive critical region of 1.7 Mb. We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy. We observed eight distinct protein-truncating mutations and three nonconservative missense mutations affecting amino acids conserved through evolution. In all families, we identified a mutation on each disease allele, either in the homozygous or in the compound heterozygous state. The CMT4C gene is strongly expressed in neural tissues, including peripheral nerve tissue. The translated protein defines a new protein family of unknown function with putative orthologues in vertebrates. Comparative sequence alignments indicate that members of this protein family contain multiple SH3 and TPR domains that are likely involved in the formation of protein complexes.
Mutations in the myotubularin-related protein 2 gene on chromosome 11q22 are known to cause autos... more Mutations in the myotubularin-related protein 2 gene on chromosome 11q22 are known to cause autosomal recessive Charcot–Marie–Tooth disease with irregularly folded myelin sheaths. We screened the coding region of the myotubularin-related protein 2 gene in a Turkish consanguineous Charcot–Marie–Tooth disease family compatible with linkage to chromosome 11q22. A homozygous cytosine to thymine missense mutation at nucleotide position 847, resulting in
Congenital muscular dystrophies (CMDs) are a genetically and clinically heterogeneous group of ne... more Congenital muscular dystrophies (CMDs) are a genetically and clinically heterogeneous group of neuromuscular disorders. Several genes encoding extracellular matrix, nuclear envelope, sarcolemmal proteins and glycosylation enzymes have been implicated in CMDs. The large overlap of clinical presentations due to mutations in different genes poses a challenge for clinicians in determining disease etiology for each patient. We investigated the use of whole exome sequencing (WES) in identifying the genetic cause of disease in 5 CMD patients from 3 families who presented with highly similar clinical features, including early-onset rapidly progressive weakness without brain or eye abnormalities. Whole exome sequencing was performed on DNA from affected individuals. Potential functional impacts of mutations were investigated by immunostaining on available muscle biopsies. Pathogenic mutations in 3 different genes, DYSF, FKTN, and ISPD were identified in each family. Mutation in DYSF led to a...
Limb-girdle muscular dystrophies constitute a broad range of clinical and genetic entities. We ha... more Limb-girdle muscular dystrophies constitute a broad range of clinical and genetic entities. We have evaluated 38 autosomal recessive limb-girdle muscular dystrophy (LGMD2) families by linkage analysis for the known loci of LGMD2A-F and protein studies using immunofluorescence and western blotting of the sarcoglycan complex. One index case in each family was investigated thoroughly. The age of onset and the current
Cardiomyopathy (CMP) in childhood is an etiologically heterogeneous group of cardiac disease, inc... more Cardiomyopathy (CMP) in childhood is an etiologically heterogeneous group of cardiac disease, including many genetic, metabolic, neuromuscular and environmental causes. The goal of this study is to determine the underlying causes and clinical characteristics of children presenting with CMP to a tertiary medical center in Turkey. We analyzed the data of 109 patients retrospectively, who presented with CMP as an initial feature, and without a specific diagnosis, between May 2007 and May 2012. Patients who already developed CMP during the course of a diagnosed disease were excluded from the study. Among 109 patients, 57 were male, and 52 were female. Most of the patients were symptomatic (n = 59) in the first year of life (54.1%). The patients were subdivided into three groups, as dilated CMP (n = 69, 63.3%), hypertrophic CMP (n = 32, 9.4%), and restrictive CMP (n = 8, 7.3%). The etiology remained unknown in 68.8% of all cases. Inborn errors of metabolism (n = 16) and cardiac diseases ...
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Papers by Haluk Topaloglu