The Experts below are selected from a list of 171 Experts worldwide ranked by ideXlab platform
Xue Zhang - One of the best experts on this subject based on the ideXlab platform.
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17p13 3 genomic rearrangement in a chinese family with split hand foot malformation with long bone deficiency report of a complicated duplication with marked variation in phenotype
Orphanet Journal of Rare Diseases, 2018Co-Authors: Yuqi Shen, Zhe Liu, Fang Liu, Xiaolu Meng, Ying Zhang, Xue ZhangAbstract:Split hand/foot malformation (SHFM) is a genetically heterogeneous limb malformation with variable expressivity. SHFM with tibia or femur aplasia is called SHFM with long bone deficiency (SHFLD). 17p13.3 duplications containing BHLHA9 are associated with SHFLD. Cases with variable SHFLD phenotype and different 17p13.3 duplicated regions are reported. The severity of long bone defect could not be simply explained by BHLHA9 overdosage or 17p13.3 duplication. A four-generation Chinese SHFM family was recruited. Three family members have long bone defects, one male was severely affected with hypoplasia or aplasia in three of four limbs. Linkage analysis and direct sequencing of candidate genes were used to exclude six responsible genes/loci for isolated SHFM. Array comparative genomic hybridization (CGH) was performed to detect copy number variations on a genome-wide scale, and quantitative real-time polymerase chain reaction (qPCR) assays were designed to validate the identified copy number variation in the index and other family members. No mutations were found in genes or loci linked to isolated SHFM. A ~ 966 kb duplication was identified in 17p13.3 by array CGH, in which BHLHA9 surrounding region presented as triplication. The qPCR assays confirmed the indicated 17p13.3 duplication as well as BHLHA9 triplication in all available affected family members and other two asymptomatic carriers. Given the incomplete penetrance in SHFLD, those two carriers were regarded as non-penetrant, which suggested that the genomic rearrangement was co-segregated with malformation in this family. The present study reports an additional SHFLD family case with 17p13.3 genomic rearrangement. To our knowledge, the 966 kb genomic rearrangement is larger in size than any previously reported SHFLD-associated 17p13.3 duplication, and the present family shows marked phenotypic variability with two asymptomatic carriers and one patient with an extremely severe phenotype. This rare case provides the opportunity to identify Underlying Genotype-phenotype correlations between SHFLD and 17p13.3 genomic rearrangement.
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17p13.3 genomic rearrangement in a Chinese family with split-hand/foot malformation with long bone deficiency: report of a complicated duplication with marked variation in phenotype
BMC, 2018Co-Authors: Yuqi Shen, Zhe Liu, Fang Liu, Xiaolu Meng, Ying Zhang, Xue ZhangAbstract:Abstract Background Split hand/foot malformation (SHFM) is a genetically heterogeneous limb malformation with variable expressivity. SHFM with tibia or femur aplasia is called SHFM with long bone deficiency (SHFLD). 17p13.3 duplications containing BHLHA9 are associated with SHFLD. Cases with variable SHFLD phenotype and different 17p13.3 duplicated regions are reported. The severity of long bone defect could not be simply explained by BHLHA9 overdosage or 17p13.3 duplication. Methods A four-generation Chinese SHFM family was recruited. Three family members have long bone defects, one male was severely affected with hypoplasia or aplasia in three of four limbs. Linkage analysis and direct sequencing of candidate genes were used to exclude six responsible genes/loci for isolated SHFM. Array comparative genomic hybridization (CGH) was performed to detect copy number variations on a genome-wide scale, and quantitative real-time polymerase chain reaction (qPCR) assays were designed to validate the identified copy number variation in the index and other family members. Results No mutations were found in genes or loci linked to isolated SHFM. A ~ 966 kb duplication was identified in 17p13.3 by array CGH, in which BHLHA9 surrounding region presented as triplication. The qPCR assays confirmed the indicated 17p13.3 duplication as well as BHLHA9 triplication in all available affected family members and other two asymptomatic carriers. Given the incomplete penetrance in SHFLD, those two carriers were regarded as non-penetrant, which suggested that the genomic rearrangement was co-segregated with malformation in this family. Conclusions The present study reports an additional SHFLD family case with 17p13.3 genomic rearrangement. To our knowledge, the 966 kb genomic rearrangement is larger in size than any previously reported SHFLD-associated 17p13.3 duplication, and the present family shows marked phenotypic variability with two asymptomatic carriers and one patient with an extremely severe phenotype. This rare case provides the opportunity to identify Underlying Genotype-phenotype correlations between SHFLD and 17p13.3 genomic rearrangement
Sven C D Van Ijzendoorn - One of the best experts on this subject based on the ideXlab platform.
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a molecular mechanism Underlying Genotype specific intrahepatic cholestasis resulting from myo5b mutations
Hepatology, 2020Co-Authors: Arend W Overeem, Yiling Qiu, Fernando Cartongarcia, Changsen Leng, Karin Klappe, Just Dronkers, Naihua Hsiao, Jianshe Wang, Diego Arango, Sven C D Van IjzendoornAbstract:Background and aims Progressive familial intrahepatic cholestasis (PFIC) 6 has been associated with missense but not biallelic nonsense or frameshift mutations in MYO5B, encoding the motor protein myosin Vb (myoVb). This Genotype-phenotype correlation and the mechanism through which MYO5B mutations give rise to PFIC are not understood. The aim of this study was to determine whether the loss of myoVb or expression of patient-specific myoVb mutants can be causally related to defects in canalicular protein localization and, if so, through which mechanism. Approach and results We demonstrate that the cholestasis-associated substitution of the proline at amino acid position 600 in the myoVb protein to a leucine (P660L) caused the intracellular accumulation of bile canalicular proteins in vesicular compartments. Remarkably, the knockout of MYO5B in vitro and in vivo produced no canalicular localization defects. In contrast, the expression of myoVb mutants consisting of only the tail domain phenocopied the effects of the Myo5b-P660L mutation. Using additional myoVb and rab11a mutants, we demonstrate that motor domain-deficient myoVb inhibited the formation of specialized apical recycling endosomes and that its disrupting effect on the localization of canalicular proteins was dependent on its interaction with active rab11a and occurred at the trans-Golgi Network/recycling endosome interface. Conclusions Our results reveal a mechanism through which MYO5B motor domain mutations can cause the mislocalization of canalicular proteins in hepatocytes which, unexpectedly, does not involve myoVb loss-of-function but, as we propose, a rab11a-mediated gain-of-toxic function. The results explain why biallelic MYO5B mutations that affect the motor domain but not those that eliminate myoVb expression are associated with PFIC6.
Laurent Hebertdufresne - One of the best experts on this subject based on the ideXlab platform.
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localization epidemic transitions and unpredictability of multistrain epidemics with an Underlying Genotype network
PLOS Computational Biology, 2021Co-Authors: Blake J M Williams, Guillaume Stonge, Laurent HebertdufresneAbstract:Mathematical disease modelling has long operated under the assumption that any one infectious disease is caused by one transmissible pathogen spreading among a population. This paradigm has been useful in simplifying the biological reality of epidemics and has allowed the modelling community to focus on the complexity of other factors such as population structure and interventions. However, there is an increasing amount of evidence that the strain diversity of pathogens, and their interplay with the host immune system, can play a large role in shaping the dynamics of epidemics. Here, we introduce a disease model with an Underlying Genotype network to account for two important mechanisms. One, the disease can mutate along network pathways as it spreads in a host population. Two, the Genotype network allows us to define a genetic distance between strains and therefore to model the transcendence of immunity often observed in real world pathogens. We study the emergence of epidemics in this model, through its epidemic phase transitions, and highlight the role of the Genotype network in driving cyclicity of diseases, large scale fluctuations, sequential epidemic transitions, as well as localization around specific strains of the associated pathogen. More generally, our model illustrates the richness of behaviours that are possible even in well-mixed host populations once we consider strain diversity and go beyond the “one disease equals one pathogen” paradigm.
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emergence of multistrain epidemics with an Underlying Genotype network
ALIFE 2020: The 2020 Conference on Artificial Life, 2020Co-Authors: Blake J M Williams, Guillaume Stonge, Laurent HebertdufresneAbstract:Mathematical disease modeling has long operated under the assumption that a single disease is caused by a single pathogen spreading among a population. This paradigm has been useful in simplifying ...
Yuqi Shen - One of the best experts on this subject based on the ideXlab platform.
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17p13 3 genomic rearrangement in a chinese family with split hand foot malformation with long bone deficiency report of a complicated duplication with marked variation in phenotype
Orphanet Journal of Rare Diseases, 2018Co-Authors: Yuqi Shen, Zhe Liu, Fang Liu, Xiaolu Meng, Ying Zhang, Xue ZhangAbstract:Split hand/foot malformation (SHFM) is a genetically heterogeneous limb malformation with variable expressivity. SHFM with tibia or femur aplasia is called SHFM with long bone deficiency (SHFLD). 17p13.3 duplications containing BHLHA9 are associated with SHFLD. Cases with variable SHFLD phenotype and different 17p13.3 duplicated regions are reported. The severity of long bone defect could not be simply explained by BHLHA9 overdosage or 17p13.3 duplication. A four-generation Chinese SHFM family was recruited. Three family members have long bone defects, one male was severely affected with hypoplasia or aplasia in three of four limbs. Linkage analysis and direct sequencing of candidate genes were used to exclude six responsible genes/loci for isolated SHFM. Array comparative genomic hybridization (CGH) was performed to detect copy number variations on a genome-wide scale, and quantitative real-time polymerase chain reaction (qPCR) assays were designed to validate the identified copy number variation in the index and other family members. No mutations were found in genes or loci linked to isolated SHFM. A ~ 966 kb duplication was identified in 17p13.3 by array CGH, in which BHLHA9 surrounding region presented as triplication. The qPCR assays confirmed the indicated 17p13.3 duplication as well as BHLHA9 triplication in all available affected family members and other two asymptomatic carriers. Given the incomplete penetrance in SHFLD, those two carriers were regarded as non-penetrant, which suggested that the genomic rearrangement was co-segregated with malformation in this family. The present study reports an additional SHFLD family case with 17p13.3 genomic rearrangement. To our knowledge, the 966 kb genomic rearrangement is larger in size than any previously reported SHFLD-associated 17p13.3 duplication, and the present family shows marked phenotypic variability with two asymptomatic carriers and one patient with an extremely severe phenotype. This rare case provides the opportunity to identify Underlying Genotype-phenotype correlations between SHFLD and 17p13.3 genomic rearrangement.
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17p13.3 genomic rearrangement in a Chinese family with split-hand/foot malformation with long bone deficiency: report of a complicated duplication with marked variation in phenotype
BMC, 2018Co-Authors: Yuqi Shen, Zhe Liu, Fang Liu, Xiaolu Meng, Ying Zhang, Xue ZhangAbstract:Abstract Background Split hand/foot malformation (SHFM) is a genetically heterogeneous limb malformation with variable expressivity. SHFM with tibia or femur aplasia is called SHFM with long bone deficiency (SHFLD). 17p13.3 duplications containing BHLHA9 are associated with SHFLD. Cases with variable SHFLD phenotype and different 17p13.3 duplicated regions are reported. The severity of long bone defect could not be simply explained by BHLHA9 overdosage or 17p13.3 duplication. Methods A four-generation Chinese SHFM family was recruited. Three family members have long bone defects, one male was severely affected with hypoplasia or aplasia in three of four limbs. Linkage analysis and direct sequencing of candidate genes were used to exclude six responsible genes/loci for isolated SHFM. Array comparative genomic hybridization (CGH) was performed to detect copy number variations on a genome-wide scale, and quantitative real-time polymerase chain reaction (qPCR) assays were designed to validate the identified copy number variation in the index and other family members. Results No mutations were found in genes or loci linked to isolated SHFM. A ~ 966 kb duplication was identified in 17p13.3 by array CGH, in which BHLHA9 surrounding region presented as triplication. The qPCR assays confirmed the indicated 17p13.3 duplication as well as BHLHA9 triplication in all available affected family members and other two asymptomatic carriers. Given the incomplete penetrance in SHFLD, those two carriers were regarded as non-penetrant, which suggested that the genomic rearrangement was co-segregated with malformation in this family. Conclusions The present study reports an additional SHFLD family case with 17p13.3 genomic rearrangement. To our knowledge, the 966 kb genomic rearrangement is larger in size than any previously reported SHFLD-associated 17p13.3 duplication, and the present family shows marked phenotypic variability with two asymptomatic carriers and one patient with an extremely severe phenotype. This rare case provides the opportunity to identify Underlying Genotype-phenotype correlations between SHFLD and 17p13.3 genomic rearrangement
Arend W Overeem - One of the best experts on this subject based on the ideXlab platform.
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a molecular mechanism Underlying Genotype specific intrahepatic cholestasis resulting from myo5b mutations
Hepatology, 2020Co-Authors: Arend W Overeem, Yiling Qiu, Fernando Cartongarcia, Changsen Leng, Karin Klappe, Just Dronkers, Naihua Hsiao, Jianshe Wang, Diego Arango, Sven C D Van IjzendoornAbstract:Background and aims Progressive familial intrahepatic cholestasis (PFIC) 6 has been associated with missense but not biallelic nonsense or frameshift mutations in MYO5B, encoding the motor protein myosin Vb (myoVb). This Genotype-phenotype correlation and the mechanism through which MYO5B mutations give rise to PFIC are not understood. The aim of this study was to determine whether the loss of myoVb or expression of patient-specific myoVb mutants can be causally related to defects in canalicular protein localization and, if so, through which mechanism. Approach and results We demonstrate that the cholestasis-associated substitution of the proline at amino acid position 600 in the myoVb protein to a leucine (P660L) caused the intracellular accumulation of bile canalicular proteins in vesicular compartments. Remarkably, the knockout of MYO5B in vitro and in vivo produced no canalicular localization defects. In contrast, the expression of myoVb mutants consisting of only the tail domain phenocopied the effects of the Myo5b-P660L mutation. Using additional myoVb and rab11a mutants, we demonstrate that motor domain-deficient myoVb inhibited the formation of specialized apical recycling endosomes and that its disrupting effect on the localization of canalicular proteins was dependent on its interaction with active rab11a and occurred at the trans-Golgi Network/recycling endosome interface. Conclusions Our results reveal a mechanism through which MYO5B motor domain mutations can cause the mislocalization of canalicular proteins in hepatocytes which, unexpectedly, does not involve myoVb loss-of-function but, as we propose, a rab11a-mediated gain-of-toxic function. The results explain why biallelic MYO5B mutations that affect the motor domain but not those that eliminate myoVb expression are associated with PFIC6.
