240
Xenopus
membrane-bound proteins important for vision and neural
function, respectively. As predicted, emc1 depletion in RPE
cells led to mis-localized rhodopsin and nAChR. EMC1
patient phenotypes can therefore be explained by the defects
in proper localization of these functionally important multipass transmembrane proteins during development (Marquez
et al. 2020).
16.5. WHERE TO GO FROM HERE? THE FUTURE
OF STUDYING CHD IN XENOPUS
With estimates of 10,000 patient-parent trios needed to
achieve 80% saturation of genes associated with syndromic
CHD cases (Jin et al. 2017), there is much more work to
be done identifying new candidate genes, connecting their
contributions to CHD/HTX, and understanding the role
each gene plays in CHD/HTX etiology. Both clinicians
and scientists beneft as they learn more about the genetic,
molecular, and cellular mechanisms underlying the etiology
of CHD/HTX. Clinicians will have access to an increasing list of studied CHD/HTX genes they can refer to when
admitting, diagnosing, and treating new CHD patients.
The list, along with basic science research of underlying
molecular mechanisms, can help improve targeted patient
care, potentially predict whether a patient may have undiagnosed extracardiac issues, and guide preventative care for
CHD comorbidities/shared etiologies with other anomalies
and neurodevelopmental disorders. These combined efforts
also will aid genetic counseling of couples for their family
planning.
Continued recruitment and genomic analysis of patients
will continue to provide researchers with new genes to gain
better insights into human health, development, and basic
cell biology. These developmental phenotype and mechanistic studies provide scaffolding for asking new lines of questions understudied in developmental biology. Such questions
shed light on shared molecular pathways between CHD/
HTX and associated diseases, new molecular functions of
understudied genes, and unexpected roles of known molecules in development.
REFERENCES
Abbot, Maude E. 1915. “Congenital Cardiac Disease.” In Osler’s
Modern Medicine, 4th ed., 323–448. Philadelphia: Lea &
Febiger.
Abu-Safeh, Leen, May Alrashed, Shamsa Anazi, Hisham Alkuraya,
Arif O. Khan, Mohammed Al-Owain, Jawahir Al-Zahrani,
et al. 2013. “Autozygome-Guided Exome Sequencing in
Retinal Dystrophy Patients Reveals Pathogenetic Mutations
and Novel Candidate Disease Genes.” Genome Research 23
(2): 236–247. https://doi.org/10.1101/gr.144105.112 .
Afzelius, Björn A. 1977. “A Human Syndrome Caused by Immotile
Cilia.” Obstetrical and Gynecological Survey 32 (1): 49–50.
https://doi.org/10.1097/00006254-197701000-00024 .
Alkan, Can, Bradley P. Coe, and Evan E. Eichler. 2011. “Genome
Structural Variation Discovery and Genotyping.” Nature
Reviews Genetics 12 (5): 363–376. https://doi.org/10.1038/
nrg2958.
Bartlett, Heather L., Lillian Sutherland, Sandra J. Kolker, Chelsea
Welp, Urszula Tajchman, Vera Desmarais, and Daniel L.
Weeks. 2007. “Transient Early Embryonic Expression of
Nkx2–5 Mutations Linked to Congenital Heart Defects
in Human Causes Heart Defects in Xenopus laevis.”
Developmental Dynamics 236 (9): 2475–2484. https://doi.
org/10.1002/dvdy.21244.
Barton, Kevin, Natarajan Muthusamy, Christopher Fischer,
Chao Nan Ting, Theresa L. Walunas, Lewis L. Lanier, and
Jeffrey M. Leiden. 1998. “The Ets-1 Transcription Factor
Is Required for the Development of Natural Killer Cells in
Mice.” Immunity 9 (4): 555–563. https://doi.org/10.1016/
S1074-7613(00)80638-X .
Basson, Craig T., David R. Bachinsky, Robert C. Lin, Tatjana Levi,
Jacob A. Elkins, Johann Soults, David Grayzel, et al. 1997.
“Mutations in Human Cause Limb and Cardiac Malformation
in Holt-Oram Syndrome.” Nature Genetics 15 (1): 30–35.
https://doi.org/10.1038/ng0197-30 .
Belgareh, Naïma, Gwénaël Rabut, Siau Wei Baï, Megan Van
Overbeek, Joël Beaudouin, Nathalie Daigle, Olga V.
Zatsepina, et al. 2001. “An Evolutionarily Conserved NPC
Subcomplex, Which Redistributes in Part to Kinetochores in
Mammalian Cells.” Journal of Cell Biology 154 (6): 1147–
1160. https://doi.org/10.1083/jcb.200101081 .
Bennett, Eric P., Ulla Mandel, Henrik Clausen, Thomas A.
Gerken, Timothy A. Fritz, and Lawrence A. Tabak. 2012.
“Control of Mucin-Type O-Glycosylation: A Classif cation
of the Polypeptide GalNAc-Transferase Gene Family.”
Glycobiology 22 (6): 736–756. https://doi.org/10.1093/
glycob/cwr182 .
Benson, D. Woodrow, G. Michael Silberbach, Ann KavanaughMcHugh, Carol Cottrill, Yizhong Zhang, Steve Riggs,
Octavia Smalls, et al. 1999. “Mutations in the Cardiac
Transcription Factor NKX2.5 Affect Diverse Cardiac
Developmental Pathways.” Journal of Clinical Investigation
104 (11): 1567–73. https://doi.org/10.1172/JCI8154 .
Bhattacharya, Dipankan, Chris A. Marfo, Davis Li, Maura Lane, and
Mustafa K. Khokha. 2015. “CRISPR/Cas9: An Inexpensive,
Effcient Loss of Function Tool to Screen Human Disease
Genes in Xenopus.” Developmental Biology 408 (2): 196–
204. https://doi.org/10.1016/j.ydbio.2015.11.003.
Blalock, Alfred, and Helen B. Taussig. 1945. “The Surgical
Treatment of Maformations of the Heart.” Journal of the
American Medical Association 128 (3): 189. https://doi.
org/10.1001/jama.1945.02860200029009 .
Blum, Martin, Tina Beyer, Thomas Weber, Philipp Vick, Philipp
Andre, Eva Bitzer, and Axel Schweickert. 2009. “Xenopus,
an Ideal Model System to Study Vertebrate Left-Right
Asymmetry.” Developmental Dynamics 238 (6): 1215–1225.
https://doi.org/10.1002/dvdy.21855 .
Bodmer, R. 1993. “The Gene Tinman Is Required for Specif cation
of the Heart and Visceral Muscles in Drosophila.”
Development 118 (3): 719–729.
Bodmer, R., L. Y. Jan, and Y. N. Jan. 1990. “A New HomeoboxContaining Gene, Msh-2, Is Transiently Expressed Early
during Mesoderm Formation of Drosophila.” Development
110 (3): 661–669.
Boskovski, Marko T., Shiaulou Yuan, Nis Borbye Pedersen,
Christoffer Knak Goth, Svetlana Makova, Henrik Clausen,
Martina Brueckner, and Mustafa K. Khokha. 2013. “The
Heterotaxy Gene GALNT11 Glycosylates Notch to
Orchestrate Cilia Type and Laterality.” Nature 504 (7480):
456–459. https://doi.org/10.1038/nature12723 .
Breslow, David K., Elena F. Koslover, Federica Seydel, Andrew
J. Spakowitz, and Maxence V. Nachury. 2013. “An In Vitro
Xenopus
membrane-bound proteins important for vision and neural
function, respectively. As predicted, emc1 depletion in RPE
cells led to mis-localized rhodopsin and nAChR. EMC1
patient phenotypes can therefore be explained by the defects
in proper localization of these functionally important multipass transmembrane proteins during development (Marquez
et al. 2020).
16.5. WHERE TO GO FROM HERE? THE FUTURE
OF STUDYING CHD IN XENOPUS
With estimates of 10,000 patient-parent trios needed to
achieve 80% saturation of genes associated with syndromic
CHD cases (Jin et al. 2017), there is much more work to
be done identifying new candidate genes, connecting their
contributions to CHD/HTX, and understanding the role
each gene plays in CHD/HTX etiology. Both clinicians
and scientists beneft as they learn more about the genetic,
molecular, and cellular mechanisms underlying the etiology
of CHD/HTX. Clinicians will have access to an increasing list of studied CHD/HTX genes they can refer to when
admitting, diagnosing, and treating new CHD patients.
The list, along with basic science research of underlying
molecular mechanisms, can help improve targeted patient
care, potentially predict whether a patient may have undiagnosed extracardiac issues, and guide preventative care for
CHD comorbidities/shared etiologies with other anomalies
and neurodevelopmental disorders. These combined efforts
also will aid genetic counseling of couples for their family
planning.
Continued recruitment and genomic analysis of patients
will continue to provide researchers with new genes to gain
better insights into human health, development, and basic
cell biology. These developmental phenotype and mechanistic studies provide scaffolding for asking new lines of questions understudied in developmental biology. Such questions
shed light on shared molecular pathways between CHD/
HTX and associated diseases, new molecular functions of
understudied genes, and unexpected roles of known molecules in development.
REFERENCES
Abbot, Maude E. 1915. “Congenital Cardiac Disease.” In Osler’s
Modern Medicine, 4th ed., 323–448. Philadelphia: Lea &
Febiger.
Abu-Safeh, Leen, May Alrashed, Shamsa Anazi, Hisham Alkuraya,
Arif O. Khan, Mohammed Al-Owain, Jawahir Al-Zahrani,
et al. 2013. “Autozygome-Guided Exome Sequencing in
Retinal Dystrophy Patients Reveals Pathogenetic Mutations
and Novel Candidate Disease Genes.” Genome Research 23
(2): 236–247. https://doi.org/10.1101/gr.144105.112 .
Afzelius, Björn A. 1977. “A Human Syndrome Caused by Immotile
Cilia.” Obstetrical and Gynecological Survey 32 (1): 49–50.
https://doi.org/10.1097/00006254-197701000-00024 .
Alkan, Can, Bradley P. Coe, and Evan E. Eichler. 2011. “Genome
Structural Variation Discovery and Genotyping.” Nature
Reviews Genetics 12 (5): 363–376. https://doi.org/10.1038/
nrg2958.
Bartlett, Heather L., Lillian Sutherland, Sandra J. Kolker, Chelsea
Welp, Urszula Tajchman, Vera Desmarais, and Daniel L.
Weeks. 2007. “Transient Early Embryonic Expression of
Nkx2–5 Mutations Linked to Congenital Heart Defects
in Human Causes Heart Defects in Xenopus laevis.”
Developmental Dynamics 236 (9): 2475–2484. https://doi.
org/10.1002/dvdy.21244.
Barton, Kevin, Natarajan Muthusamy, Christopher Fischer,
Chao Nan Ting, Theresa L. Walunas, Lewis L. Lanier, and
Jeffrey M. Leiden. 1998. “The Ets-1 Transcription Factor
Is Required for the Development of Natural Killer Cells in
Mice.” Immunity 9 (4): 555–563. https://doi.org/10.1016/
S1074-7613(00)80638-X .
Basson, Craig T., David R. Bachinsky, Robert C. Lin, Tatjana Levi,
Jacob A. Elkins, Johann Soults, David Grayzel, et al. 1997.
“Mutations in Human Cause Limb and Cardiac Malformation
in Holt-Oram Syndrome.” Nature Genetics 15 (1): 30–35.
https://doi.org/10.1038/ng0197-30 .
Belgareh, Naïma, Gwénaël Rabut, Siau Wei Baï, Megan Van
Overbeek, Joël Beaudouin, Nathalie Daigle, Olga V.
Zatsepina, et al. 2001. “An Evolutionarily Conserved NPC
Subcomplex, Which Redistributes in Part to Kinetochores in
Mammalian Cells.” Journal of Cell Biology 154 (6): 1147–
1160. https://doi.org/10.1083/jcb.200101081 .
Bennett, Eric P., Ulla Mandel, Henrik Clausen, Thomas A.
Gerken, Timothy A. Fritz, and Lawrence A. Tabak. 2012.
“Control of Mucin-Type O-Glycosylation: A Classif cation
of the Polypeptide GalNAc-Transferase Gene Family.”
Glycobiology 22 (6): 736–756. https://doi.org/10.1093/
glycob/cwr182 .
Benson, D. Woodrow, G. Michael Silberbach, Ann KavanaughMcHugh, Carol Cottrill, Yizhong Zhang, Steve Riggs,
Octavia Smalls, et al. 1999. “Mutations in the Cardiac
Transcription Factor NKX2.5 Affect Diverse Cardiac
Developmental Pathways.” Journal of Clinical Investigation
104 (11): 1567–73. https://doi.org/10.1172/JCI8154 .
Bhattacharya, Dipankan, Chris A. Marfo, Davis Li, Maura Lane, and
Mustafa K. Khokha. 2015. “CRISPR/Cas9: An Inexpensive,
Effcient Loss of Function Tool to Screen Human Disease
Genes in Xenopus.” Developmental Biology 408 (2): 196–
204. https://doi.org/10.1016/j.ydbio.2015.11.003.
Blalock, Alfred, and Helen B. Taussig. 1945. “The Surgical
Treatment of Maformations of the Heart.” Journal of the
American Medical Association 128 (3): 189. https://doi.
org/10.1001/jama.1945.02860200029009 .
Blum, Martin, Tina Beyer, Thomas Weber, Philipp Vick, Philipp
Andre, Eva Bitzer, and Axel Schweickert. 2009. “Xenopus,
an Ideal Model System to Study Vertebrate Left-Right
Asymmetry.” Developmental Dynamics 238 (6): 1215–1225.
https://doi.org/10.1002/dvdy.21855 .
Bodmer, R. 1993. “The Gene Tinman Is Required for Specif cation
of the Heart and Visceral Muscles in Drosophila.”
Development 118 (3): 719–729.
Bodmer, R., L. Y. Jan, and Y. N. Jan. 1990. “A New HomeoboxContaining Gene, Msh-2, Is Transiently Expressed Early
during Mesoderm Formation of Drosophila.” Development
110 (3): 661–669.
Boskovski, Marko T., Shiaulou Yuan, Nis Borbye Pedersen,
Christoffer Knak Goth, Svetlana Makova, Henrik Clausen,
Martina Brueckner, and Mustafa K. Khokha. 2013. “The
Heterotaxy Gene GALNT11 Glycosylates Notch to
Orchestrate Cilia Type and Laterality.” Nature 504 (7480):
456–459. https://doi.org/10.1038/nature12723 .
Breslow, David K., Elena F. Koslover, Federica Seydel, Andrew
J. Spakowitz, and Maxence V. Nachury. 2013. “An In Vitro