I am trilingual and love working with people.Before acting, I analyze all the possilities. There are never problems, only solutions. So I work hard to make things happen. My expertise lies in teaching (school, lifesaving and swimming) and research (leukodystrophy and ovarian cancer), but I am also experienced in customer service and management.My ability to work in a team was reinforced during numerous academic and professional projects.My goals is to gain experience in my field to be able to train future employees.
Objective. In an attempt to analyze more profoundly aberrant DNA hypomethylation in epithelial ov... more Objective. In an attempt to analyze more profoundly aberrant DNA hypomethylation in epithelial ovarian cancer (EOC), we applied a novel genome-based approach which includes expression profiling following pharmacologic stimulation of DNA methylation with the methyl donor S-adenosyl-L-methionine (SAM). Methods. Four different EOC cell lines (OVCAR3, SKOV3, TOV21 and TOV112) were treated with SAM, and gene expression profiling was performed in SAM-treated and control EOC cells. Genes, downregulated upon SAM treatment were considered as potentially hypomethylated in EOC. DNA hypomethylation was independently validated in ovarian tumor and control tissues by bisulfite sequencing PCR (BSP). Results. Among the genes identified, one of particular interest was the type II serine protease TMPRSS3 gene variants A and D (TMPRSS3-A/D), previously recognized as overexpressed in EOC and representing potential EOC therapeutic targets. Consecutive BSP analysis demonstrated that the common putative promoter region of the TMPRSS3-A/D gene variants was significantly hypomethylated in high-grade serous EOC tumors , compared to low-malignant potential ovarian tumors and normal ovarian tissue. Conclusions. Our data imply that TMPRSS3-A/D overexpression in EOC is probably due to hypomethyla-tion of their control region thus indicating that TMPRSS3-A/D variants could also represent novel molecular targets for epigenetic therapy of late stages of the disease. Our results also suggest that the frequently observed upregulation of different members of the type II serine proteases gene family in advanced cancer could be due to aberrant DNA hypomethylation. Furthermore, our study introduces a promising discovery approach that could be used for the identification of hypomethylated genes in different experimental cell models.
Objective. In an attempt to analyze more profoundly aberrant DNA hypomethylation in epithelial ov... more Objective. In an attempt to analyze more profoundly aberrant DNA hypomethylation in epithelial ovarian cancer (EOC), we applied a novel genome-based approach which includes expression profiling following pharmacologic stimulation of DNA methylation with the methyl donor S-adenosyl-L-methionine (SAM). Methods. Four different EOC cell lines (OVCAR3, SKOV3, TOV21 and TOV112) were treated with SAM, and gene expression profiling was performed in SAM-treated and control EOC cells. Genes, downregulated upon SAM treatment were considered as potentially hypomethylated in EOC. DNA hypomethylation was independently validated in ovarian tumor and control tissues by bisulfite sequencing PCR (BSP). Results. Among the genes identified, one of particular interest was the type II serine protease TMPRSS3 gene variants A and D (TMPRSS3-A/D), previously recognized as overexpressed in EOC and representing potential EOC therapeutic targets. Consecutive BSP analysis demonstrated that the common putative promoter region of the TMPRSS3-A/D gene variants was significantly hypomethylated in high-grade serous EOC tumors , compared to low-malignant potential ovarian tumors and normal ovarian tissue. Conclusions. Our data imply that TMPRSS3-A/D overexpression in EOC is probably due to hypomethyla-tion of their control region thus indicating that TMPRSS3-A/D variants could also represent novel molecular targets for epigenetic therapy of late stages of the disease. Our results also suggest that the frequently observed upregulation of different members of the type II serine proteases gene family in advanced cancer could be due to aberrant DNA hypomethylation. Furthermore, our study introduces a promising discovery approach that could be used for the identification of hypomethylated genes in different experimental cell models.
To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyeli... more To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy caused by mutations in POLR3A or POLR3B. We performed a multinational cross-sectional observational study of the clinical, radiologic, and molecular characteristics of 105 mutation-proven cases. The majority of patients presented before 6 years with gross motor delay or regression. Ten percent had an onset beyond 10 years. The disease course was milder in patients with POLR3B than in patients with POLR3A mutations. Other than the typical neurologic, dental, and endocrine features, myopia was seen in almost all and short stature in 50%. Dental and hormonal findings were not invariably present. Mutations in POLR3A and POLR3B were distributed throughout the genes. Except for French Canadian patients, patients from European backgrounds were more likely to have POLR3B mutations than other populations. Most patients carried the ...
A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA p... more A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes' availability leading to two different clinical conditions and to shed some light on the pathophysiological mechanism of one of the most common hypomyelinatin...
POLR3-related (or 4H) leukodystrophy is an autosomal recessive disorder caused by mutations in PO... more POLR3-related (or 4H) leukodystrophy is an autosomal recessive disorder caused by mutations in POLR3A or POLR3B and is characterized by neurological and non-neurological features. In a small proportion of patients, no mutation in either gene or only one mutation is found. Analysis of the POLR3B cDNA revealed a large deletion of exons 21-22 in one case and of exons 26-27 in another case. These are the first reports of long deletions causing POLR3-related leukodystrophy, suggesting that deletions and duplications in POLR3A or POLR3B should be investigated in patients with a compatible phenotype, especially if one pathogenic variant has been identified.
Objective This study aims to ascertain frequency of mutations in POLR3A or POLR3B, which are asso... more Objective This study aims to ascertain frequency of mutations in POLR3A or POLR3B, which are associated with 4H leukodystrophy, in a cohort of patients with unclassified hypomyelination. Methods and Results In a cohort of 22 patients with the magnetic resonance imaging (MRI) diagnosis of unclassified hypomyelination and without typical clinical signs, we evaluated clinical and MRI features. Developmental delay or intellectual disability, ataxia, and spasticity were frequent symptoms. POLR3A and POLR3B were sequenced. A compound heterozygote mutation in POLR3B was found in only one patient. Additional investigations allowed a definitive diagnosis in 10 patients. Conclusion Mutations in POLR3A or POLR3B are rare in patients with unclassified hypomyelination, and alternative diagnoses should be considered first.
We present a series of unrelated patients with isolated hypomyelination, with or without mild cer... more We present a series of unrelated patients with isolated hypomyelination, with or without mild cerebellar atrophy, and de novo TUBB4A mutations. Patients in 2 large institutional review board-approved leukodystrophy bioregistries at Children's National Medical Center and Montreal Children's Hospital with similar MRI features had whole-exome sequencing performed. MRIs and clinical information were reviewed. Five patients who presented with hypomyelination without the classic basal ganglia abnormalities were found to have novel TUBB4A mutations through whole-exome sequencing. Clinical and imaging characteristics were reviewed suggesting a spectrum of clinical manifestations. Hypomyelinating leukodystrophies remain a diagnostic challenge with a large percentage of unresolved cases. This finding expands the phenotype of TUBB4A-related hypomyelinating conditions beyond hypomyelination with atrophy of the basal ganglia and cerebellum. TUBB4A mutation screening should be considered ...
We report a case of mild cavitating leukoencephalopathy associated with a homozygous c.755A &... more We report a case of mild cavitating leukoencephalopathy associated with a homozygous c.755A > G (p.Asp252Gly) NDUFS1 mutation in a 7-year old boy. Biochemical analysis confirmed an isolated reduction in complex I activity. Magnetic resonance imaging of the brain showed a diffuse cystic leukoencephalopathy with the involvement of the corpus callosum and sparing of the gray matter. The clinical course was marked by an acute presentation of neurological deficits at 24 months followed by recurrent episodes of mild neurological deterioration, subsequent remissions, and prolonged periods of stability. This is one of the mildest known clinical presentations of complex I deficiency secondary to mutations in NDUFS1, expanding the clinical spectrum and natural history of this disorder. Consideration of clinical variability needs to be taken into account in patient management and family counseling.
To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyeli... more To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy caused by mutations in POLR3A or POLR3B. We performed a multinational cross-sectional observational study of the clinical, radiologic, and molecular characteristics of 105 mutation-proven cases. The majority of patients presented before 6 years with gross motor delay or regression. Ten percent had an onset beyond 10 years. The disease course was milder in patients with POLR3B than in patients with POLR3A mutations. Other than the typical neurologic, dental, and endocrine features, myopia was seen in almost all and short stature in 50%. Dental and hormonal findings were not invariably present. Mutations in POLR3A and POLR3B were distributed throughout the genes. Except for French Canadian patients, patients from European backgrounds were more likely to have POLR3B mutations than other populations. Most patients carried the ...
Objective. In an attempt to analyze more profoundly aberrant DNA hypomethylation in epithelial ov... more Objective. In an attempt to analyze more profoundly aberrant DNA hypomethylation in epithelial ovarian cancer (EOC), we applied a novel genome-based approach which includes expression profiling following pharmacologic stimulation of DNA methylation with the methyl donor S-adenosyl-L-methionine (SAM). Methods. Four different EOC cell lines (OVCAR3, SKOV3, TOV21 and TOV112) were treated with SAM, and gene expression profiling was performed in SAM-treated and control EOC cells. Genes, downregulated upon SAM treatment were considered as potentially hypomethylated in EOC. DNA hypomethylation was independently validated in ovarian tumor and control tissues by bisulfite sequencing PCR (BSP). Results. Among the genes identified, one of particular interest was the type II serine protease TMPRSS3 gene variants A and D (TMPRSS3-A/D), previously recognized as overexpressed in EOC and representing potential EOC therapeutic targets. Consecutive BSP analysis demonstrated that the common putative promoter region of the TMPRSS3-A/D gene variants was significantly hypomethylated in high-grade serous EOC tumors , compared to low-malignant potential ovarian tumors and normal ovarian tissue. Conclusions. Our data imply that TMPRSS3-A/D overexpression in EOC is probably due to hypomethyla-tion of their control region thus indicating that TMPRSS3-A/D variants could also represent novel molecular targets for epigenetic therapy of late stages of the disease. Our results also suggest that the frequently observed upregulation of different members of the type II serine proteases gene family in advanced cancer could be due to aberrant DNA hypomethylation. Furthermore, our study introduces a promising discovery approach that could be used for the identification of hypomethylated genes in different experimental cell models.
Objective. In an attempt to analyze more profoundly aberrant DNA hypomethylation in epithelial ov... more Objective. In an attempt to analyze more profoundly aberrant DNA hypomethylation in epithelial ovarian cancer (EOC), we applied a novel genome-based approach which includes expression profiling following pharmacologic stimulation of DNA methylation with the methyl donor S-adenosyl-L-methionine (SAM). Methods. Four different EOC cell lines (OVCAR3, SKOV3, TOV21 and TOV112) were treated with SAM, and gene expression profiling was performed in SAM-treated and control EOC cells. Genes, downregulated upon SAM treatment were considered as potentially hypomethylated in EOC. DNA hypomethylation was independently validated in ovarian tumor and control tissues by bisulfite sequencing PCR (BSP). Results. Among the genes identified, one of particular interest was the type II serine protease TMPRSS3 gene variants A and D (TMPRSS3-A/D), previously recognized as overexpressed in EOC and representing potential EOC therapeutic targets. Consecutive BSP analysis demonstrated that the common putative promoter region of the TMPRSS3-A/D gene variants was significantly hypomethylated in high-grade serous EOC tumors , compared to low-malignant potential ovarian tumors and normal ovarian tissue. Conclusions. Our data imply that TMPRSS3-A/D overexpression in EOC is probably due to hypomethyla-tion of their control region thus indicating that TMPRSS3-A/D variants could also represent novel molecular targets for epigenetic therapy of late stages of the disease. Our results also suggest that the frequently observed upregulation of different members of the type II serine proteases gene family in advanced cancer could be due to aberrant DNA hypomethylation. Furthermore, our study introduces a promising discovery approach that could be used for the identification of hypomethylated genes in different experimental cell models.
To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyeli... more To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy caused by mutations in POLR3A or POLR3B. We performed a multinational cross-sectional observational study of the clinical, radiologic, and molecular characteristics of 105 mutation-proven cases. The majority of patients presented before 6 years with gross motor delay or regression. Ten percent had an onset beyond 10 years. The disease course was milder in patients with POLR3B than in patients with POLR3A mutations. Other than the typical neurologic, dental, and endocrine features, myopia was seen in almost all and short stature in 50%. Dental and hormonal findings were not invariably present. Mutations in POLR3A and POLR3B were distributed throughout the genes. Except for French Canadian patients, patients from European backgrounds were more likely to have POLR3B mutations than other populations. Most patients carried the ...
A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA p... more A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes' availability leading to two different clinical conditions and to shed some light on the pathophysiological mechanism of one of the most common hypomyelinatin...
POLR3-related (or 4H) leukodystrophy is an autosomal recessive disorder caused by mutations in PO... more POLR3-related (or 4H) leukodystrophy is an autosomal recessive disorder caused by mutations in POLR3A or POLR3B and is characterized by neurological and non-neurological features. In a small proportion of patients, no mutation in either gene or only one mutation is found. Analysis of the POLR3B cDNA revealed a large deletion of exons 21-22 in one case and of exons 26-27 in another case. These are the first reports of long deletions causing POLR3-related leukodystrophy, suggesting that deletions and duplications in POLR3A or POLR3B should be investigated in patients with a compatible phenotype, especially if one pathogenic variant has been identified.
Objective This study aims to ascertain frequency of mutations in POLR3A or POLR3B, which are asso... more Objective This study aims to ascertain frequency of mutations in POLR3A or POLR3B, which are associated with 4H leukodystrophy, in a cohort of patients with unclassified hypomyelination. Methods and Results In a cohort of 22 patients with the magnetic resonance imaging (MRI) diagnosis of unclassified hypomyelination and without typical clinical signs, we evaluated clinical and MRI features. Developmental delay or intellectual disability, ataxia, and spasticity were frequent symptoms. POLR3A and POLR3B were sequenced. A compound heterozygote mutation in POLR3B was found in only one patient. Additional investigations allowed a definitive diagnosis in 10 patients. Conclusion Mutations in POLR3A or POLR3B are rare in patients with unclassified hypomyelination, and alternative diagnoses should be considered first.
We present a series of unrelated patients with isolated hypomyelination, with or without mild cer... more We present a series of unrelated patients with isolated hypomyelination, with or without mild cerebellar atrophy, and de novo TUBB4A mutations. Patients in 2 large institutional review board-approved leukodystrophy bioregistries at Children's National Medical Center and Montreal Children's Hospital with similar MRI features had whole-exome sequencing performed. MRIs and clinical information were reviewed. Five patients who presented with hypomyelination without the classic basal ganglia abnormalities were found to have novel TUBB4A mutations through whole-exome sequencing. Clinical and imaging characteristics were reviewed suggesting a spectrum of clinical manifestations. Hypomyelinating leukodystrophies remain a diagnostic challenge with a large percentage of unresolved cases. This finding expands the phenotype of TUBB4A-related hypomyelinating conditions beyond hypomyelination with atrophy of the basal ganglia and cerebellum. TUBB4A mutation screening should be considered ...
We report a case of mild cavitating leukoencephalopathy associated with a homozygous c.755A &... more We report a case of mild cavitating leukoencephalopathy associated with a homozygous c.755A > G (p.Asp252Gly) NDUFS1 mutation in a 7-year old boy. Biochemical analysis confirmed an isolated reduction in complex I activity. Magnetic resonance imaging of the brain showed a diffuse cystic leukoencephalopathy with the involvement of the corpus callosum and sparing of the gray matter. The clinical course was marked by an acute presentation of neurological deficits at 24 months followed by recurrent episodes of mild neurological deterioration, subsequent remissions, and prolonged periods of stability. This is one of the mildest known clinical presentations of complex I deficiency secondary to mutations in NDUFS1, expanding the clinical spectrum and natural history of this disorder. Consideration of clinical variability needs to be taken into account in patient management and family counseling.
To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyeli... more To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy caused by mutations in POLR3A or POLR3B. We performed a multinational cross-sectional observational study of the clinical, radiologic, and molecular characteristics of 105 mutation-proven cases. The majority of patients presented before 6 years with gross motor delay or regression. Ten percent had an onset beyond 10 years. The disease course was milder in patients with POLR3B than in patients with POLR3A mutations. Other than the typical neurologic, dental, and endocrine features, myopia was seen in almost all and short stature in 50%. Dental and hormonal findings were not invariably present. Mutations in POLR3A and POLR3B were distributed throughout the genes. Except for French Canadian patients, patients from European backgrounds were more likely to have POLR3B mutations than other populations. Most patients carried the ...
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