Buket Basmanav | Universitätsmedizin Göttingen (original) (raw)

Papers by Buket Basmanav

Research paper thumbnail of Assessment of the Genetic Spectrum of Uncombable Hair Syndrome in a Cohort of 107 Individuals

JAMA Dermatology

ImportanceUncombable hair syndrome (UHS) is a rare hair shaft anomaly that manifests during infan... more ImportanceUncombable hair syndrome (UHS) is a rare hair shaft anomaly that manifests during infancy and is characterized by dry, frizzy, and wiry hair that cannot be combed flat. Only about 100 known cases have been reported so far.ObjectiveTo elucidate the genetic spectrum of UHS.Design, Setting, and ParticipantsThis cohort study includes 107 unrelated index patients with a suspected diagnosis of UHS and family members who were recruited worldwide from January 2013 to December 2021. Participants of all ages, races, and ethnicities were recruited at referral centers or were enrolled on their own initiative following personal contact with the authors. Genetic analyses were conducted in Germany from January 2014 to December 2021.Main Outcomes and MeasuresClinical photographs, Sanger or whole-exome sequencing and array-based genotyping of DNA extracted from blood or saliva samples, and 3-dimensional protein modeling. Descriptive statistics, such as frequency counts, were used to descri...

Research paper thumbnail of Translational impact of omics studies in alopecia areata: recent advances and future perspectives

Expert Review of Clinical Immunology

Research paper thumbnail of Phänotypische Vielfalt bei Varianten im TP63 ‐Gen

JDDG: Journal der Deutschen Dermatologischen Gesellschaft

Research paper thumbnail of Protein nanobarcodes enable single-step multiplexed fluorescence imaging

Multiplexed cellular imaging typically relies on the sequential application of detection probes, ... more Multiplexed cellular imaging typically relies on the sequential application of detection probes, such as antibodies or DNA barcodes, which is complex and time-consuming. To address this, we developed here protein nanobarcodes, composed of combinations of epitopes recognized by specific sets of nanobodies. The nanobarcodes are read in a single imaging step, relying on nanobodies conjugated to distinct fluorophores, which enables a precise analysis of large numbers of protein combinations.

Research paper thumbnail of Four hypotrichosis families with mutations in the gene LSS presenting with and without neurodevelopmental phenotypes

American Journal of Medical Genetics Part A, 2021

Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bon... more Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany Givi Zhvania Academic Clinic of Pediatrics, Tbilisi State Medical University, Tbilisi, Georgia Cologne Center for Genomics, University of Cologne, Cologne, Germany Department of Pediatrics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany Department of Dermatology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Institute of Structural Biology, University of Bonn, School of Medicine, Bonn, Germany

Research paper thumbnail of Atrichia with papular lesions: a differential diagnosis of alopecia universalis not to be missed

Journal of the European Academy of Dermatology and Venereology, 2021

Atrichia with papular lesions (APL, OMIM 209500) is a rare autosomal recessive disease that is ch... more Atrichia with papular lesions (APL, OMIM 209500) is a rare autosomal recessive disease that is characterized by irreversible hair loss usually taking place in the first months of life1 . Papular lesions are frequently observed in patients appearing at approximately 2 years of age and consisting of cysts filled with keratin. Pathogenic variants in the hairless gene (HR) have been reported in APL2-5 HR encodes a zinc-finger transcription factor that is highly expressed in brain and skin. Lack of expression of this factor causes disruption of the normal growth cycle of the mature hair follicle resulting in alopecia and development of dermal cysts. We observed an unsuspected case of APL in a patient misdiagnosed as alopecia universalis for several decades.

Research paper thumbnail of A nanobody-based fluorescent reporter reveals human α-synuclein in the cell cytosol

ABSTRACTAggregation and spreading of α-Synuclein (αSyn) are hallmarks of several neurodegenerativ... more ABSTRACTAggregation and spreading of α-Synuclein (αSyn) are hallmarks of several neurodegenerative diseases, thus monitoring human αSyn (hαSyn) in animal models or cell cultures is vital for the field. However, the detection of native hαSyn in such systems is challenging. We found that the nanobody NbSyn87, previously-described to bind hαSyn, also shows cross-reactivity for the proteasomal subunit Rpn10. As such, when the NbSyn87 is expressed in the absence of hαSyn, it is continuously degraded by the proteasome, while it is stabilized when it binds to hαSyn. Here, we exploited this feature to design a new Fluorescent Reporter for hαSyn (FluoReSyn) by coupling NbSyn87 to fluorescent proteins, which results in fluorescence signal fluctuations depending on the presence and amounts of intracellular hαSyn. We characterized this biosensor in cells and tissues, and finally, revealed the presence of transmittable αSyn in human cerebrospinal fluid demonstrating the potential of FluoReSyn fo...

Research paper thumbnail of Identification of a novel mutation in RIPK4 in a kindred with phenotypic features of Bartsocas-Papas and CHAND syndromes

American journal of medical genetics. Part A, Jan 30, 2015

Three children from an expanded consanguineous Kuwaiti kindred presented with ankyloblepharon, sp... more Three children from an expanded consanguineous Kuwaiti kindred presented with ankyloblepharon, sparse and curly hair, and hypoplastic nails, suggestive of CHAND syndrome (OMIM 214350) that belongs to the heterogeneous spectrum of ectodermal dysplasias. After exclusion of pathogenic mutations in TP63 we performed homozygosity mapping, followed by exome sequencing of one affected individual. We initially identified three homozygous mutations in the linked region, located in PWP2, MX2 and RIPK4. Recently, mutations in RIPK4 have been reported in Bartsocas-Papas syndrome (OMIM 263650) that shows overlapping clinical symptoms with the phenotype observed in the affected individuals studied here. Subsequent analysis of affected and non-affected family members showed that mutation c.850G>A (p.Glu284Lys) in RIPK4 was in complete segregation with the disease phenotype, in accordance with an autosomal recessive inheritance pattern, thus supporting pathogenicity of this variant. Interestingl...

Research paper thumbnail of Sequential growth factor delivery from complexed microspheres for bone tissue engineering

Research paper thumbnail of Insights Into the Biology of Persistent Chemotherapy-Induced Alopecia via Genomic Approaches—An Avenue to Clinical Translation?

Research paper thumbnail of Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome

American journal of human genetics, 2016

Uncombable hair syndrome (UHS), also known as "spun glass hair syndrome," "pili tr... more Uncombable hair syndrome (UHS), also known as "spun glass hair syndrome," "pili trianguli et canaliculi," or "cheveux incoiffables" is a rare anomaly of the hair shaft that occurs in children and improves with age. UHS is characterized by dry, frizzy, spangly, and often fair hair that is resistant to being combed flat. Until now, both simplex and familial UHS-affected case subjects with autosomal-dominant as well as -recessive inheritance have been reported. However, none of these case subjects were linked to a molecular genetic cause. Here, we report the identification of UHS-causative mutations located in the three genes PADI3 (peptidylarginine deiminase 3), TGM3 (transglutaminase 3), and TCHH (trichohyalin) in a total of 11 children. All of these individuals carry homozygous or compound heterozygous mutations in one of these three genes, indicating an autosomal-recessive inheritance pattern in the majority of UHS case subjects. The two enzymes PADI3 ...

Research paper thumbnail of Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome

American journal of human genetics, 2016

Uncombable hair syndrome (UHS), also known as "spun glass hair syndrome," "pili tr... more Uncombable hair syndrome (UHS), also known as "spun glass hair syndrome," "pili trianguli et canaliculi," or "cheveux incoiffables" is a rare anomaly of the hair shaft that occurs in children and improves with age. UHS is characterized by dry, frizzy, spangly, and often fair hair that is resistant to being combed flat. Until now, both simplex and familial UHS-affected case subjects with autosomal-dominant as well as -recessive inheritance have been reported. However, none of these case subjects were linked to a molecular genetic cause. Here, we report the identification of UHS-causative mutations located in the three genes PADI3 (peptidylarginine deiminase 3), TGM3 (transglutaminase 3), and TCHH (trichohyalin) in a total of 11 children. All of these individuals carry homozygous or compound heterozygous mutations in one of these three genes, indicating an autosomal-recessive inheritance pattern in the majority of UHS case subjects. The two enzymes PADI3 ...

Research paper thumbnail of Investigation of the role of TCF4 rare sequence variants in schizophrenia

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2015

Transcription factor 4 (TCF4) is one of the most robust of all reported schizophrenia risk loci a... more Transcription factor 4 (TCF4) is one of the most robust of all reported schizophrenia risk loci and is supported by several genetic and functional lines of evidence. While numerous studies have implicated common genetic variation at TCF4 in schizophrenia risk, the role of rare, small-sized variants at this locus-such as single nucleotide variants and short indels which are below the resolution of chip-based arrays requires further exploration. The aim of the present study was to investigate the association between rare TCF4 sequence variants and schizophrenia. Exon-targeted resequencing was performed in 190 German schizophrenia patients. Six rare variants at the coding exons and flanking sequences of the TCF4 gene were identified, including two missense variants and one splice site variant. These six variants were then pooled with nine additional rare variants identified in 379 European participants of the 1000 Genomes Project, and all 15 variants were genotyped in an independent German sample (n = 1,808 patients; n = 2,261 controls). These data were then analyzed using six statistical methods developed for the association analysis of rare variants. No significant association (P < 0.05) was found. However, the results from our association and power analyses suggest that further research into the possible involvement of rare TCF4 sequence variants in schizophrenia risk is warranted by the assessment of larger cohorts with higher statistical power to identify rare variant associations. © 2015 Wiley Periodicals, Inc.

Research paper thumbnail of Nanobiomaterials: a review of the existing science and technology, and new approaches

Journal of Biomaterials Science, Polymer Edition, 2006

Research paper thumbnail of Biomaterials and tissue engineering research in Turkey: The METU Biomat Center experience

Biotechnology Journal, 2009

Research paper thumbnail of Investigation of the role of TCF4 rare sequence variants in schizophrenia

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2015

Transcription factor 4 (TCF4) is one of the most robust of all reported schizophrenia risk loci a... more Transcription factor 4 (TCF4) is one of the most robust of all reported schizophrenia risk loci and is supported by several genetic and functional lines of evidence. While numerous studies have implicated common genetic variation at TCF4 in schizophrenia risk, the role of rare, small-sized variants at this locus-such as single nucleotide variants and short indels which are below the resolution of chip-based arrays requires further exploration. The aim of the present study was to investigate the association between rare TCF4 sequence variants and schizophrenia. Exon-targeted resequencing was performed in 190 German schizophrenia patients. Six rare variants at the coding exons and flanking sequences of the TCF4 gene were identified, including two missense variants and one splice site variant. These six variants were then pooled with nine additional rare variants identified in 379 European participants of the 1000 Genomes Project, and all 15 variants were genotyped in an independent German sample (n = 1,808 patients; n = 2,261 controls). These data were then analyzed using six statistical methods developed for the association analysis of rare variants. No significant association (P < 0.05) was found. However, the results from our association and power analyses suggest that further research into the possible involvement of rare TCF4 sequence variants in schizophrenia risk is warranted by the assessment of larger cohorts with higher statistical power to identify rare variant associations. © 2015 Wiley Periodicals, Inc.

Research paper thumbnail of Pathogenicity of POFUT1 in Dowling-Degos Disease: Additional Mutations and Clinical Overlap with Reticulate Acropigmentation of Kitamura

Journal of Investigative Dermatology, 2014

ABSTRACT Journal of Investigative Dermatology accepted article preview online, 17 September 2014.... more ABSTRACT Journal of Investigative Dermatology accepted article preview online, 17 September 2014. doi:10.1038/jid.2014.406.

Research paper thumbnail of Investigation of the involvement of MIR185 and its target genes in the development of schizophrenia

Schizophrenia is a complex neuropsychiatric disorder of unclear etiology. The strongest known gen... more Schizophrenia is a complex neuropsychiatric disorder of unclear etiology. The strongest known genetic risk factor is the 22q11.2 microdeletion. Research has yet to confirm which genes within the deletion region are implicated in schizophrenia. The minimal 1.5 megabase deletion contains MIR185, which encodes microRNA 185. We determined miR-185 expression in embryonic and adult mouse brains. Common and rare variants at this locus were then investigated using a human genetics approach. First, we performed gene-based analyses for MIR185 common variants and target genes using Psychiatric Genomics Consortium genome-wide association data. Second, MIR185 was resequenced in German patients (n = 1000) and controls (n = 500). We followed up promising variants by genotyping an additional European sample (patients, n = 3598; controls, n = 4082). In situ hybridization in mice revealed miR-185 expression in brain regions implicated in schizophrenia. Gene-based tests revealed association between common variants in 3 MIR185 target genes (ATAT1, SH3PXD2A, NTRK3) and schizophrenia. Further analyses in mice revealed overlapping expression patterns for these target genes and miR-185. Resequencing identified 2 rare patient-specific novel variants flanking MIR185. However, follow-up genotyping provided no further evidence of their involvement in schizophrenia. Power to detect rare variant associations was limited. Human genetic analyses generated no evidence of the involvement of MIR185 in schizophrenia. However, the expression patterns of miR-185 and its target genes in mice, and the genetic association results for the 3 target genes, suggest that further research into the involvement of miR-185 and its downstream pathways in schizophrenia is warranted.

Research paper thumbnail of Immunochip-Based Analysis: High-Density Genotyping of Immune-Related Loci Sheds Further Light on the Autoimmune Genetic Architecture of Alopecia Areata

Journal of Investigative Dermatology, 2014

Research paper thumbnail of ZNF804A genetic variation (rs1344706) affects brain grey but not white matter in schizophrenia and healthy subjects

Psychological Medicine, 2014

Research paper thumbnail of Assessment of the Genetic Spectrum of Uncombable Hair Syndrome in a Cohort of 107 Individuals

JAMA Dermatology

ImportanceUncombable hair syndrome (UHS) is a rare hair shaft anomaly that manifests during infan... more ImportanceUncombable hair syndrome (UHS) is a rare hair shaft anomaly that manifests during infancy and is characterized by dry, frizzy, and wiry hair that cannot be combed flat. Only about 100 known cases have been reported so far.ObjectiveTo elucidate the genetic spectrum of UHS.Design, Setting, and ParticipantsThis cohort study includes 107 unrelated index patients with a suspected diagnosis of UHS and family members who were recruited worldwide from January 2013 to December 2021. Participants of all ages, races, and ethnicities were recruited at referral centers or were enrolled on their own initiative following personal contact with the authors. Genetic analyses were conducted in Germany from January 2014 to December 2021.Main Outcomes and MeasuresClinical photographs, Sanger or whole-exome sequencing and array-based genotyping of DNA extracted from blood or saliva samples, and 3-dimensional protein modeling. Descriptive statistics, such as frequency counts, were used to descri...

Research paper thumbnail of Translational impact of omics studies in alopecia areata: recent advances and future perspectives

Expert Review of Clinical Immunology

Research paper thumbnail of Phänotypische Vielfalt bei Varianten im TP63 ‐Gen

JDDG: Journal der Deutschen Dermatologischen Gesellschaft

Research paper thumbnail of Protein nanobarcodes enable single-step multiplexed fluorescence imaging

Multiplexed cellular imaging typically relies on the sequential application of detection probes, ... more Multiplexed cellular imaging typically relies on the sequential application of detection probes, such as antibodies or DNA barcodes, which is complex and time-consuming. To address this, we developed here protein nanobarcodes, composed of combinations of epitopes recognized by specific sets of nanobodies. The nanobarcodes are read in a single imaging step, relying on nanobodies conjugated to distinct fluorophores, which enables a precise analysis of large numbers of protein combinations.

Research paper thumbnail of Four hypotrichosis families with mutations in the gene LSS presenting with and without neurodevelopmental phenotypes

American Journal of Medical Genetics Part A, 2021

Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bon... more Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany Givi Zhvania Academic Clinic of Pediatrics, Tbilisi State Medical University, Tbilisi, Georgia Cologne Center for Genomics, University of Cologne, Cologne, Germany Department of Pediatrics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany Department of Dermatology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Institute of Structural Biology, University of Bonn, School of Medicine, Bonn, Germany

Research paper thumbnail of Atrichia with papular lesions: a differential diagnosis of alopecia universalis not to be missed

Journal of the European Academy of Dermatology and Venereology, 2021

Atrichia with papular lesions (APL, OMIM 209500) is a rare autosomal recessive disease that is ch... more Atrichia with papular lesions (APL, OMIM 209500) is a rare autosomal recessive disease that is characterized by irreversible hair loss usually taking place in the first months of life1 . Papular lesions are frequently observed in patients appearing at approximately 2 years of age and consisting of cysts filled with keratin. Pathogenic variants in the hairless gene (HR) have been reported in APL2-5 HR encodes a zinc-finger transcription factor that is highly expressed in brain and skin. Lack of expression of this factor causes disruption of the normal growth cycle of the mature hair follicle resulting in alopecia and development of dermal cysts. We observed an unsuspected case of APL in a patient misdiagnosed as alopecia universalis for several decades.

Research paper thumbnail of A nanobody-based fluorescent reporter reveals human α-synuclein in the cell cytosol

ABSTRACTAggregation and spreading of α-Synuclein (αSyn) are hallmarks of several neurodegenerativ... more ABSTRACTAggregation and spreading of α-Synuclein (αSyn) are hallmarks of several neurodegenerative diseases, thus monitoring human αSyn (hαSyn) in animal models or cell cultures is vital for the field. However, the detection of native hαSyn in such systems is challenging. We found that the nanobody NbSyn87, previously-described to bind hαSyn, also shows cross-reactivity for the proteasomal subunit Rpn10. As such, when the NbSyn87 is expressed in the absence of hαSyn, it is continuously degraded by the proteasome, while it is stabilized when it binds to hαSyn. Here, we exploited this feature to design a new Fluorescent Reporter for hαSyn (FluoReSyn) by coupling NbSyn87 to fluorescent proteins, which results in fluorescence signal fluctuations depending on the presence and amounts of intracellular hαSyn. We characterized this biosensor in cells and tissues, and finally, revealed the presence of transmittable αSyn in human cerebrospinal fluid demonstrating the potential of FluoReSyn fo...

Research paper thumbnail of Identification of a novel mutation in RIPK4 in a kindred with phenotypic features of Bartsocas-Papas and CHAND syndromes

American journal of medical genetics. Part A, Jan 30, 2015

Three children from an expanded consanguineous Kuwaiti kindred presented with ankyloblepharon, sp... more Three children from an expanded consanguineous Kuwaiti kindred presented with ankyloblepharon, sparse and curly hair, and hypoplastic nails, suggestive of CHAND syndrome (OMIM 214350) that belongs to the heterogeneous spectrum of ectodermal dysplasias. After exclusion of pathogenic mutations in TP63 we performed homozygosity mapping, followed by exome sequencing of one affected individual. We initially identified three homozygous mutations in the linked region, located in PWP2, MX2 and RIPK4. Recently, mutations in RIPK4 have been reported in Bartsocas-Papas syndrome (OMIM 263650) that shows overlapping clinical symptoms with the phenotype observed in the affected individuals studied here. Subsequent analysis of affected and non-affected family members showed that mutation c.850G>A (p.Glu284Lys) in RIPK4 was in complete segregation with the disease phenotype, in accordance with an autosomal recessive inheritance pattern, thus supporting pathogenicity of this variant. Interestingl...

Research paper thumbnail of Sequential growth factor delivery from complexed microspheres for bone tissue engineering

Research paper thumbnail of Insights Into the Biology of Persistent Chemotherapy-Induced Alopecia via Genomic Approaches—An Avenue to Clinical Translation?

Research paper thumbnail of Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome

American journal of human genetics, 2016

Uncombable hair syndrome (UHS), also known as "spun glass hair syndrome," "pili tr... more Uncombable hair syndrome (UHS), also known as "spun glass hair syndrome," "pili trianguli et canaliculi," or "cheveux incoiffables" is a rare anomaly of the hair shaft that occurs in children and improves with age. UHS is characterized by dry, frizzy, spangly, and often fair hair that is resistant to being combed flat. Until now, both simplex and familial UHS-affected case subjects with autosomal-dominant as well as -recessive inheritance have been reported. However, none of these case subjects were linked to a molecular genetic cause. Here, we report the identification of UHS-causative mutations located in the three genes PADI3 (peptidylarginine deiminase 3), TGM3 (transglutaminase 3), and TCHH (trichohyalin) in a total of 11 children. All of these individuals carry homozygous or compound heterozygous mutations in one of these three genes, indicating an autosomal-recessive inheritance pattern in the majority of UHS case subjects. The two enzymes PADI3 ...

Research paper thumbnail of Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome

American journal of human genetics, 2016

Uncombable hair syndrome (UHS), also known as "spun glass hair syndrome," "pili tr... more Uncombable hair syndrome (UHS), also known as "spun glass hair syndrome," "pili trianguli et canaliculi," or "cheveux incoiffables" is a rare anomaly of the hair shaft that occurs in children and improves with age. UHS is characterized by dry, frizzy, spangly, and often fair hair that is resistant to being combed flat. Until now, both simplex and familial UHS-affected case subjects with autosomal-dominant as well as -recessive inheritance have been reported. However, none of these case subjects were linked to a molecular genetic cause. Here, we report the identification of UHS-causative mutations located in the three genes PADI3 (peptidylarginine deiminase 3), TGM3 (transglutaminase 3), and TCHH (trichohyalin) in a total of 11 children. All of these individuals carry homozygous or compound heterozygous mutations in one of these three genes, indicating an autosomal-recessive inheritance pattern in the majority of UHS case subjects. The two enzymes PADI3 ...

Research paper thumbnail of Investigation of the role of TCF4 rare sequence variants in schizophrenia

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2015

Transcription factor 4 (TCF4) is one of the most robust of all reported schizophrenia risk loci a... more Transcription factor 4 (TCF4) is one of the most robust of all reported schizophrenia risk loci and is supported by several genetic and functional lines of evidence. While numerous studies have implicated common genetic variation at TCF4 in schizophrenia risk, the role of rare, small-sized variants at this locus-such as single nucleotide variants and short indels which are below the resolution of chip-based arrays requires further exploration. The aim of the present study was to investigate the association between rare TCF4 sequence variants and schizophrenia. Exon-targeted resequencing was performed in 190 German schizophrenia patients. Six rare variants at the coding exons and flanking sequences of the TCF4 gene were identified, including two missense variants and one splice site variant. These six variants were then pooled with nine additional rare variants identified in 379 European participants of the 1000 Genomes Project, and all 15 variants were genotyped in an independent German sample (n = 1,808 patients; n = 2,261 controls). These data were then analyzed using six statistical methods developed for the association analysis of rare variants. No significant association (P < 0.05) was found. However, the results from our association and power analyses suggest that further research into the possible involvement of rare TCF4 sequence variants in schizophrenia risk is warranted by the assessment of larger cohorts with higher statistical power to identify rare variant associations. © 2015 Wiley Periodicals, Inc.

Research paper thumbnail of Nanobiomaterials: a review of the existing science and technology, and new approaches

Journal of Biomaterials Science, Polymer Edition, 2006

Research paper thumbnail of Biomaterials and tissue engineering research in Turkey: The METU Biomat Center experience

Biotechnology Journal, 2009

Research paper thumbnail of Investigation of the role of TCF4 rare sequence variants in schizophrenia

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2015

Transcription factor 4 (TCF4) is one of the most robust of all reported schizophrenia risk loci a... more Transcription factor 4 (TCF4) is one of the most robust of all reported schizophrenia risk loci and is supported by several genetic and functional lines of evidence. While numerous studies have implicated common genetic variation at TCF4 in schizophrenia risk, the role of rare, small-sized variants at this locus-such as single nucleotide variants and short indels which are below the resolution of chip-based arrays requires further exploration. The aim of the present study was to investigate the association between rare TCF4 sequence variants and schizophrenia. Exon-targeted resequencing was performed in 190 German schizophrenia patients. Six rare variants at the coding exons and flanking sequences of the TCF4 gene were identified, including two missense variants and one splice site variant. These six variants were then pooled with nine additional rare variants identified in 379 European participants of the 1000 Genomes Project, and all 15 variants were genotyped in an independent German sample (n = 1,808 patients; n = 2,261 controls). These data were then analyzed using six statistical methods developed for the association analysis of rare variants. No significant association (P < 0.05) was found. However, the results from our association and power analyses suggest that further research into the possible involvement of rare TCF4 sequence variants in schizophrenia risk is warranted by the assessment of larger cohorts with higher statistical power to identify rare variant associations. © 2015 Wiley Periodicals, Inc.

Research paper thumbnail of Pathogenicity of POFUT1 in Dowling-Degos Disease: Additional Mutations and Clinical Overlap with Reticulate Acropigmentation of Kitamura

Journal of Investigative Dermatology, 2014

ABSTRACT Journal of Investigative Dermatology accepted article preview online, 17 September 2014.... more ABSTRACT Journal of Investigative Dermatology accepted article preview online, 17 September 2014. doi:10.1038/jid.2014.406.

Research paper thumbnail of Investigation of the involvement of MIR185 and its target genes in the development of schizophrenia

Schizophrenia is a complex neuropsychiatric disorder of unclear etiology. The strongest known gen... more Schizophrenia is a complex neuropsychiatric disorder of unclear etiology. The strongest known genetic risk factor is the 22q11.2 microdeletion. Research has yet to confirm which genes within the deletion region are implicated in schizophrenia. The minimal 1.5 megabase deletion contains MIR185, which encodes microRNA 185. We determined miR-185 expression in embryonic and adult mouse brains. Common and rare variants at this locus were then investigated using a human genetics approach. First, we performed gene-based analyses for MIR185 common variants and target genes using Psychiatric Genomics Consortium genome-wide association data. Second, MIR185 was resequenced in German patients (n = 1000) and controls (n = 500). We followed up promising variants by genotyping an additional European sample (patients, n = 3598; controls, n = 4082). In situ hybridization in mice revealed miR-185 expression in brain regions implicated in schizophrenia. Gene-based tests revealed association between common variants in 3 MIR185 target genes (ATAT1, SH3PXD2A, NTRK3) and schizophrenia. Further analyses in mice revealed overlapping expression patterns for these target genes and miR-185. Resequencing identified 2 rare patient-specific novel variants flanking MIR185. However, follow-up genotyping provided no further evidence of their involvement in schizophrenia. Power to detect rare variant associations was limited. Human genetic analyses generated no evidence of the involvement of MIR185 in schizophrenia. However, the expression patterns of miR-185 and its target genes in mice, and the genetic association results for the 3 target genes, suggest that further research into the involvement of miR-185 and its downstream pathways in schizophrenia is warranted.

Research paper thumbnail of Immunochip-Based Analysis: High-Density Genotyping of Immune-Related Loci Sheds Further Light on the Autoimmune Genetic Architecture of Alopecia Areata

Journal of Investigative Dermatology, 2014

Research paper thumbnail of ZNF804A genetic variation (rs1344706) affects brain grey but not white matter in schizophrenia and healthy subjects

Psychological Medicine, 2014