Susan Slaugenhaupt - Academia.edu (original) (raw)

Papers by Susan Slaugenhaupt

Research paper thumbnail of Primary cilia defects causing mitral valve prolapse

Science Translational Medicine, 2019

Genetic variations in primary cilia genes cause defects during valve morphogenesis that can progr... more Genetic variations in primary cilia genes cause defects during valve morphogenesis that can progress to mitral valve prolapse in the adult.

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Research paper thumbnail of Mutations in DCHS1 cause mitral valve prolapse

Nature, 2015

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Research paper thumbnail of Early evidence of delayed oligodendrocyte maturation in the mouse model of mucolipidosis type IV

Disease Models & Mechanisms

Mucolipidosis type IV (MLIV) is a lysosomal disease caused by mutations in the MCOLN1 gene that e... more Mucolipidosis type IV (MLIV) is a lysosomal disease caused by mutations in the MCOLN1 gene that encodes the endolysosomal transient receptor potential channel mucolipin-1, or TRPML1. MLIV results in developmental delay, motor and cognitive impairments, and vision loss. Brain abnormalities include thinning and malformation of the corpus callosum, white matter abnormalities, accumulation of undegraded intracellular “storage” material and cerebellar atrophy in older patients. Identification of the early events in the MLIV course is key to understanding the disease and deploying therapies. Mcoln1−/- mouse model reproduces all major aspects of the human disease. We have previously reported hypomyelination in the MLIV mouse brain. Here we investigated the onset of hypomyelination and compared oligodendrocyte maturation between the cortex/forebrain and cerebellum. We found significant delays in expression of mature oligodendrocyte markers Mag, Mbp, and Mobp in the Mcoln1−/-cortex manifesti...

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Research paper thumbnail of MCOLN1 gene therapy corrects neurologic dysfunction in the mouse model of mucolipidosis IV

Human Molecular Genetics

Mucolipidosis IV (MLIV) is an orphan disease leading to debilitating psychomotor deficits and vis... more Mucolipidosis IV (MLIV) is an orphan disease leading to debilitating psychomotor deficits and vision loss. It is caused by loss-of-function mutations in the MCOLN1 gene that encodes the lysosomal transient receptor potential channel mucolipin1, or TRPML1. With no existing therapy, the unmet need in this disease is very high. Here, we showed that AAV-mediated CNS-targeted gene transfer of the human MCOLN1 gene rescued motor function and alleviated brain pathology in the MLIV mouse model. Using the AAV-PHP.b vector in symptomatic mice, we showed long-term reversal of declined motor function and significant delay of paralysis. Next, using self-complementary AAV9 clinical candidate vector, we showed that its intracerebroventricular administration in post-natal day 1 mice significantly improved motor function, myelination and reduced lysosomal storage load in the MLIV mouse brain. Based on our data and general advancements in the gene therapy field, we propose scAAV9-mediated CSF-targete...

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Research paper thumbnail of MCOLN1 gene-replacement therapy corrects neurologic dysfunction in the mouse model of mucolipidosis IV

Mucolipidosis IV (MLIV, OMIM 252650) is an orphan disease leading to debilitating psychomotor def... more Mucolipidosis IV (MLIV, OMIM 252650) is an orphan disease leading to debilitating psychomotor deficits and vision loss. It is caused by loss-of-function mutations in the MCOLN1 gene that encodes thethe lysosomal transient receptor potential channel mucolipin 1 (TRPML1). With no existing therapy, the unmet need in this disease is very high. Here we show that AAV-mediated gene transfer of the human MCOLN1 gene rescues motor function and alleviates brain pathology in the Mcoln1−/− MLIV mouse model. Using the AAV-PHP.b vector for initial proof-of-principle experiments in symptomatic mice, we showed long-term reversal of declined motor function and significant delay of paralysis. Next, we designed self-complimentary AAV9 vector for clinical use and showed that its intracerebroventricular administration in post-natal day 1 mice significantly improved motor function and myelination and reduced lysosomal storage load in the MLIV mouse brain. We also showed that CNS targeted gene transfer is...

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Research paper thumbnail of Mitral Valve Prolapse is Associated with Dysregulated β-catenin Activities

Structural Heart

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Research paper thumbnail of Fingolimod Phosphate Inhibits Astrocyte Inflammatory Activity in Mucolipidosis IV

Human molecular genetics, Jan 16, 2018

Mucolipidosis IV (MLIV) is an orphan neurodevelopmental disease that causes severe neurologic dys... more Mucolipidosis IV (MLIV) is an orphan neurodevelopmental disease that causes severe neurologic dysfunction and loss of vision. Currently there is no therapy for MLIV. It is caused by loss of function of the lysosomal channel mucolipin-1, also known as TRPML1. Knockout of the Mcoln1 gene in a mouse model mirrors clinical and neuropathological signs in humans. Using this model, we previously observed robust activation of microglia and astrocytes in early symptomatic stages of disease. Here we investigate the consequence of mucolipin-1 loss on astrocyte inflammatory activation in vivo and in vitro and apply a pharmacological approach to restore Mcoln1-/- astrocyte homeostasis using a clinically approved immunomodulator, fingolimod. We found that Mcoln1-/- mice over-express numerous pro-inflammatory cytokines, some of which were also over-expressed in astrocyte cultures. Changes in the cytokine profile in Mcoln1-/- astrocytes are concomitant with changes in phospho-protein signaling, inc...

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Research paper thumbnail of Robust lysosomal calcium signaling through channel TRPML1 is impaired by lysosomal lipid accumulation

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Feb 13, 2017

The transient receptor potential cation channel mucolipin 1 (TRPML1) channel is a conduit for lys... more The transient receptor potential cation channel mucolipin 1 (TRPML1) channel is a conduit for lysosomal calcium efflux, and channel activity may be affected by lysosomal contents. The lysosomes of retinal pigmented epithelial (RPE) cells are particularly susceptible to build-up of lysosomal waste products because they must degrade the outer segments phagocytosed daily from adjacent photoreceptors; incomplete degradation leads to accumulation of lipid waste in lysosomes. This study asks whether stimulation of TRPML1 can release lysosomal calcium in RPE cells and whether such release is affected by lysosomal accumulations. The TRPML agonist ML-SA1 raised cytoplasmic calcium levels in mouse RPE cells, hesRPE cells, and ARPE-19 cells; this increase was rapid, robust, reversible, and reproducible. The increase was not altered by extracellular calcium removal or by thapsigargin but was eliminated by lysosomal rupture with glycyl-l-phenylalanine-β-naphthylamide. Treatment with desipramine ...

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Research paper thumbnail of New insights into mitral valve dystrophy: a Filamin-A genotype–phenotype and outcome study

European Heart Journal

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Research paper thumbnail of Familial dysautonomia: History, genotype, phenotype and translational research

Progress in Neurobiology, 2016

Familial dysautonomia (FD) is a rare neurological disorder caused by a splice mutation in the IKB... more Familial dysautonomia (FD) is a rare neurological disorder caused by a splice mutation in the IKBKAP gene. The mutation arose in the 1500s within the small Jewish founder population in Eastern Europe and became prevalent during the period of rapid population expansion within the Pale of Settlement. The carrier rate is 1:32 in Jews descending from this region. The mutation results in a tissue-specific deficiency in IKAP, a protein involved in the development and survival of neurons. Patients homozygous for the mutations are born with multiple lesions affecting mostly sensory (afferent) fibers, which leads to widespread organ dysfunction and increased mortality. Neurodegenerative features of the disease include progressive optic atrophy and worsening gait ataxia. Here we review the progress made in the last decade to better understand the genotype and phenotype. We also discuss the challenges of conducting controlled clinical trials in this rare medically fragile population. Meanwhile, the search for better treatments as well as a neuroprotective agent is ongoing.

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Research paper thumbnail of Mapping of the gene for the Mel{sub 1a}-melatonin receptor to human chromosome 4 (MTNR1A) and mouse chromosome 8 (Mtnr1a)

Genomics, 1995

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Research paper thumbnail of The cloning and expression of a sodium channel beta 1-subunit cDNA from human brain

Human Molecular Genetics, Jul 1, 1993

Electrical excitability of neurons and muscle cells is mediated largely through the actions of th... more Electrical excitability of neurons and muscle cells is mediated largely through the actions of the voltage-gated sodium channel. Initiation and propagation of the action potential is a direct result of the precisely controlled inward flux of sodium through these channels. Much attention has been paid to the sodium channel alpha-subunit, the major, pore-forming component. However, alpha-subunits are associated with one or more smaller beta-subunits, which have been implicated in the critical fine tuning of the gating properties of the channel. To investigate the properties of the beta-subunit, we have isolated a cDNA encoding the human brain beta 1-subunit and assigned the corresponding gene to chromosome 19. We have also examined the effects of expressing the brain beta 1-subunit on the kinetics of a coexpressed muscle sodium channel alpha-subunit. Our results underscore the functional importance of the beta 1-subunit and imply a conserved mechanism for the interaction of the beta 1-subunit with different alpha-subunits.

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Research paper thumbnail of Methods for detecting mutations associated with familial dysautonomia

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Research paper thumbnail of Kits for detecting polymorphisms associated with familial dysautonomia

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Research paper thumbnail of Dinucleotide repeat polymorphism for the hexabrachion gene (HXB) on chromosome 9q32�34

Human Molecular Genetics, 1992

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Research paper thumbnail of Implementation of Electronic Consent at a Biobank: An Opportunity for Precision Medicine Research

Journal of Personalized Medicine, 2016

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Research paper thumbnail of Abstract 13867: A Genome-wide Association Study of Nonsyndromic Mitral Valve Prolapse and Functional Studies of Risk Loci Provide Insight Into Underlying Biological Mechanisms

Circulation, Nov 25, 2014

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Research paper thumbnail of A Physical and Transcript Map of the MCOLN1 Gene Region on Human Chromosome 19p13.3�p13.2

Genomics, Apr 15, 2001

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Research paper thumbnail of Nucleotide sequences coding polypeptide for use in the diagnosis and treatment of genetic disorders associated with brain, vision and gastrointestinal disorders

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Research paper thumbnail of Methods for altering MRNA splicing and treating familial dysautonomia by administering kinetin, benzyladenine, and tocotrienols

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Primary cilia defects causing mitral valve prolapse

Science Translational Medicine, 2019

Genetic variations in primary cilia genes cause defects during valve morphogenesis that can progr... more Genetic variations in primary cilia genes cause defects during valve morphogenesis that can progress to mitral valve prolapse in the adult.

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Research paper thumbnail of Mutations in DCHS1 cause mitral valve prolapse

Nature, 2015

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Research paper thumbnail of Early evidence of delayed oligodendrocyte maturation in the mouse model of mucolipidosis type IV

Disease Models & Mechanisms

Mucolipidosis type IV (MLIV) is a lysosomal disease caused by mutations in the MCOLN1 gene that e... more Mucolipidosis type IV (MLIV) is a lysosomal disease caused by mutations in the MCOLN1 gene that encodes the endolysosomal transient receptor potential channel mucolipin-1, or TRPML1. MLIV results in developmental delay, motor and cognitive impairments, and vision loss. Brain abnormalities include thinning and malformation of the corpus callosum, white matter abnormalities, accumulation of undegraded intracellular “storage” material and cerebellar atrophy in older patients. Identification of the early events in the MLIV course is key to understanding the disease and deploying therapies. Mcoln1−/- mouse model reproduces all major aspects of the human disease. We have previously reported hypomyelination in the MLIV mouse brain. Here we investigated the onset of hypomyelination and compared oligodendrocyte maturation between the cortex/forebrain and cerebellum. We found significant delays in expression of mature oligodendrocyte markers Mag, Mbp, and Mobp in the Mcoln1−/-cortex manifesti...

Bookmarks Related papers MentionsView impact

Research paper thumbnail of MCOLN1 gene therapy corrects neurologic dysfunction in the mouse model of mucolipidosis IV

Human Molecular Genetics

Mucolipidosis IV (MLIV) is an orphan disease leading to debilitating psychomotor deficits and vis... more Mucolipidosis IV (MLIV) is an orphan disease leading to debilitating psychomotor deficits and vision loss. It is caused by loss-of-function mutations in the MCOLN1 gene that encodes the lysosomal transient receptor potential channel mucolipin1, or TRPML1. With no existing therapy, the unmet need in this disease is very high. Here, we showed that AAV-mediated CNS-targeted gene transfer of the human MCOLN1 gene rescued motor function and alleviated brain pathology in the MLIV mouse model. Using the AAV-PHP.b vector in symptomatic mice, we showed long-term reversal of declined motor function and significant delay of paralysis. Next, using self-complementary AAV9 clinical candidate vector, we showed that its intracerebroventricular administration in post-natal day 1 mice significantly improved motor function, myelination and reduced lysosomal storage load in the MLIV mouse brain. Based on our data and general advancements in the gene therapy field, we propose scAAV9-mediated CSF-targete...

Bookmarks Related papers MentionsView impact

Research paper thumbnail of MCOLN1 gene-replacement therapy corrects neurologic dysfunction in the mouse model of mucolipidosis IV

Mucolipidosis IV (MLIV, OMIM 252650) is an orphan disease leading to debilitating psychomotor def... more Mucolipidosis IV (MLIV, OMIM 252650) is an orphan disease leading to debilitating psychomotor deficits and vision loss. It is caused by loss-of-function mutations in the MCOLN1 gene that encodes thethe lysosomal transient receptor potential channel mucolipin 1 (TRPML1). With no existing therapy, the unmet need in this disease is very high. Here we show that AAV-mediated gene transfer of the human MCOLN1 gene rescues motor function and alleviates brain pathology in the Mcoln1−/− MLIV mouse model. Using the AAV-PHP.b vector for initial proof-of-principle experiments in symptomatic mice, we showed long-term reversal of declined motor function and significant delay of paralysis. Next, we designed self-complimentary AAV9 vector for clinical use and showed that its intracerebroventricular administration in post-natal day 1 mice significantly improved motor function and myelination and reduced lysosomal storage load in the MLIV mouse brain. We also showed that CNS targeted gene transfer is...

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Mitral Valve Prolapse is Associated with Dysregulated β-catenin Activities

Structural Heart

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Fingolimod Phosphate Inhibits Astrocyte Inflammatory Activity in Mucolipidosis IV

Human molecular genetics, Jan 16, 2018

Mucolipidosis IV (MLIV) is an orphan neurodevelopmental disease that causes severe neurologic dys... more Mucolipidosis IV (MLIV) is an orphan neurodevelopmental disease that causes severe neurologic dysfunction and loss of vision. Currently there is no therapy for MLIV. It is caused by loss of function of the lysosomal channel mucolipin-1, also known as TRPML1. Knockout of the Mcoln1 gene in a mouse model mirrors clinical and neuropathological signs in humans. Using this model, we previously observed robust activation of microglia and astrocytes in early symptomatic stages of disease. Here we investigate the consequence of mucolipin-1 loss on astrocyte inflammatory activation in vivo and in vitro and apply a pharmacological approach to restore Mcoln1-/- astrocyte homeostasis using a clinically approved immunomodulator, fingolimod. We found that Mcoln1-/- mice over-express numerous pro-inflammatory cytokines, some of which were also over-expressed in astrocyte cultures. Changes in the cytokine profile in Mcoln1-/- astrocytes are concomitant with changes in phospho-protein signaling, inc...

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Robust lysosomal calcium signaling through channel TRPML1 is impaired by lysosomal lipid accumulation

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Feb 13, 2017

The transient receptor potential cation channel mucolipin 1 (TRPML1) channel is a conduit for lys... more The transient receptor potential cation channel mucolipin 1 (TRPML1) channel is a conduit for lysosomal calcium efflux, and channel activity may be affected by lysosomal contents. The lysosomes of retinal pigmented epithelial (RPE) cells are particularly susceptible to build-up of lysosomal waste products because they must degrade the outer segments phagocytosed daily from adjacent photoreceptors; incomplete degradation leads to accumulation of lipid waste in lysosomes. This study asks whether stimulation of TRPML1 can release lysosomal calcium in RPE cells and whether such release is affected by lysosomal accumulations. The TRPML agonist ML-SA1 raised cytoplasmic calcium levels in mouse RPE cells, hesRPE cells, and ARPE-19 cells; this increase was rapid, robust, reversible, and reproducible. The increase was not altered by extracellular calcium removal or by thapsigargin but was eliminated by lysosomal rupture with glycyl-l-phenylalanine-β-naphthylamide. Treatment with desipramine ...

Bookmarks Related papers MentionsView impact

Research paper thumbnail of New insights into mitral valve dystrophy: a Filamin-A genotype–phenotype and outcome study

European Heart Journal

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Familial dysautonomia: History, genotype, phenotype and translational research

Progress in Neurobiology, 2016

Familial dysautonomia (FD) is a rare neurological disorder caused by a splice mutation in the IKB... more Familial dysautonomia (FD) is a rare neurological disorder caused by a splice mutation in the IKBKAP gene. The mutation arose in the 1500s within the small Jewish founder population in Eastern Europe and became prevalent during the period of rapid population expansion within the Pale of Settlement. The carrier rate is 1:32 in Jews descending from this region. The mutation results in a tissue-specific deficiency in IKAP, a protein involved in the development and survival of neurons. Patients homozygous for the mutations are born with multiple lesions affecting mostly sensory (afferent) fibers, which leads to widespread organ dysfunction and increased mortality. Neurodegenerative features of the disease include progressive optic atrophy and worsening gait ataxia. Here we review the progress made in the last decade to better understand the genotype and phenotype. We also discuss the challenges of conducting controlled clinical trials in this rare medically fragile population. Meanwhile, the search for better treatments as well as a neuroprotective agent is ongoing.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Mapping of the gene for the Mel{sub 1a}-melatonin receptor to human chromosome 4 (MTNR1A) and mouse chromosome 8 (Mtnr1a)

Genomics, 1995

Bookmarks Related papers MentionsView impact

Research paper thumbnail of The cloning and expression of a sodium channel beta 1-subunit cDNA from human brain

Human Molecular Genetics, Jul 1, 1993

Electrical excitability of neurons and muscle cells is mediated largely through the actions of th... more Electrical excitability of neurons and muscle cells is mediated largely through the actions of the voltage-gated sodium channel. Initiation and propagation of the action potential is a direct result of the precisely controlled inward flux of sodium through these channels. Much attention has been paid to the sodium channel alpha-subunit, the major, pore-forming component. However, alpha-subunits are associated with one or more smaller beta-subunits, which have been implicated in the critical fine tuning of the gating properties of the channel. To investigate the properties of the beta-subunit, we have isolated a cDNA encoding the human brain beta 1-subunit and assigned the corresponding gene to chromosome 19. We have also examined the effects of expressing the brain beta 1-subunit on the kinetics of a coexpressed muscle sodium channel alpha-subunit. Our results underscore the functional importance of the beta 1-subunit and imply a conserved mechanism for the interaction of the beta 1-subunit with different alpha-subunits.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Methods for detecting mutations associated with familial dysautonomia

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Kits for detecting polymorphisms associated with familial dysautonomia

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Dinucleotide repeat polymorphism for the hexabrachion gene (HXB) on chromosome 9q32�34

Human Molecular Genetics, 1992

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Implementation of Electronic Consent at a Biobank: An Opportunity for Precision Medicine Research

Journal of Personalized Medicine, 2016

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Abstract 13867: A Genome-wide Association Study of Nonsyndromic Mitral Valve Prolapse and Functional Studies of Risk Loci Provide Insight Into Underlying Biological Mechanisms

Circulation, Nov 25, 2014

Bookmarks Related papers MentionsView impact

Research paper thumbnail of A Physical and Transcript Map of the MCOLN1 Gene Region on Human Chromosome 19p13.3�p13.2

Genomics, Apr 15, 2001

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Nucleotide sequences coding polypeptide for use in the diagnosis and treatment of genetic disorders associated with brain, vision and gastrointestinal disorders

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Methods for altering MRNA splicing and treating familial dysautonomia by administering kinetin, benzyladenine, and tocotrienols

Bookmarks Related papers MentionsView impact