Erica Davis

Overview:

Two key questions thematically underscore my research in the Center for Human Disease Modeling at Duke University: First of all, how can variation at the DNA level be functionally interpreted beyond the resolution of genetics arguments alone? Secondly, once empowered with functional information about genetic variants, how can pathogenic alleles be mapped back to disease phenotypes? Using the ciliary disease module as a model system of investigation, we are using multidisciplinary tactics to address these questions and continue to harness these approaches toward the further dissection of the architecture of human genetic disease. Moreover, we have applied the in vivo tools and lessons learned from ciliary phenotypes affecting the renal, craniofacial, and central nervous systems to interrogate rare pediatric disorders characterized by these phenotypic hallmarks.


Positions:

Associate Professor of Pediatrics

Pediatrics, Neonatology
School of Medicine

Assistant Professor of Cell Biology

Cell Biology
School of Medicine

Associate Professor of Cell Biology

Cell Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2005

University of Liege (Belgium)

Postdoctoral Research Fellow, Institute Of Genetic Medicine

Johns Hopkins University

Postdoctoral Research Fellow, Cell Biology

Duke University

Grants:

Epigenetic Control of Intestinal Inflammation

Administered By
Cell Biology
Role
Collaborator
Start Date
End Date

Epigenetic control of intestinal inflammation

Administered By
Cell Biology
Role
Collaborator
Start Date
End Date

Bridge Funding Plan with Ann & Robert H Lurie Children's Hospital of Chicago

Administered By
Institutes and Centers
Awarded By
Ann & Robert H. Lurie Children's Hospital of Chicago
Role
Principal Investigator
Start Date
End Date

Genetic and Functional Dissection of Congenital Anomalies of the Brain

Administered By
Institutes and Centers
Awarded By
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
End Date

Functional Dissection of CNVs in Neurodevelopmental Traits

Administered By
Institutes and Centers
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia.

RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.
Authors
Guissart, C; Latypova, X; Rollier, P; Khan, TN; Stamberger, H; McWalter, K; Cho, MT; Kjaergaard, S; Weckhuysen, S; Lesca, G; Besnard, T; Õunap, K; Schema, L; Chiocchetti, AG; McDonald, M; de Bellescize, J; Vincent, M; Van Esch, H; Sattler, S; Forghani, I; Thiffault, I; Freitag, CM; Barbouth, DS; Cadieux-Dion, M; Willaert, R; Guillen Sacoto, MJ; Safina, NP; Dubourg, C; Grote, L; Carré, W; Saunders, C; Pajusalu, S; Farrow, E; Boland, A; Karlowicz, DH; Deleuze, J-F; Wojcik, MH; Pressman, R; Isidor, B; Vogels, A; Van Paesschen, W; Al-Gazali, L; Al Shamsi, AM; Claustres, M; Pujol, A; Sanders, SJ; Rivier, F; Leboucq, N; Cogné, B; Sasorith, S; Sanlaville, D; Retterer, K; Odent, S; Katsanis, N; Bézieau, S; Koenig, M; Davis, EE; Pasquier, L; Küry, S
MLA Citation
Guissart, Claire, et al. “Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia..” Am J Hum Genet, vol. 102, no. 5, May 2018, pp. 744–59. Pubmed, doi:10.1016/j.ajhg.2018.02.021.
URI
https://scholars.duke.edu/individual/pub1313823
PMID
29656859
Source
pubmed
Published In
Am J Hum Genet
Volume
102
Published Date
Start Page
744
End Page
759
DOI
10.1016/j.ajhg.2018.02.021

Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network.

Ocular developmental anomalies (ODA) such as anophthalmia/microphthalmia (AM) or anterior segment dysgenesis (ASD) have an estimated combined prevalence of 3.7 in 10,000 births. Mutations in SOX2 are the most frequent contributors to severe ODA, yet account for a minority of the genetic drivers. To identify novel ODA loci, we conducted targeted high-throughput sequencing of 407 candidate genes in an initial cohort of 22 sporadic ODA patients. Patched 1 (PTCH1), an inhibitor of sonic hedgehog (SHH) signaling, harbored an enrichment of rare heterozygous variants in comparison to either controls, or to the other candidate genes (four missense and one frameshift); targeted resequencing of PTCH1 in a second cohort of 48 ODA patients identified two additional rare nonsynonymous changes. Using multiple transient models and a CRISPR/Cas9-generated mutant, we show physiologically relevant phenotypes altering SHH signaling and eye development upon abrogation of ptch1 in zebrafish for which in vivo complementation assays using these models showed that all six patient missense mutations affect SHH signaling. Finally, through transcriptomic and ChIP analyses, we show that SOX2 binds to an intronic domain of the PTCH1 locus to regulate PTCH1 expression, findings that were validated both in vitro and in vivo. Together, these results demonstrate that PTCH1 mutations contribute to as much as 10% of ODA, identify the SHH signaling pathway as a novel effector of SOX2 activity during human ocular development, and indicate that ODA is likely the result of overactive SHH signaling in humans harboring mutations in either PTCH1 or SOX2.
Authors
Chassaing, N; Davis, EE; McKnight, KL; Niederriter, AR; Causse, A; David, V; Desmaison, A; Lamarre, S; Vincent-Delorme, C; Pasquier, L; Coubes, C; Lacombe, D; Rossi, M; Dufier, J-L; Dollfus, H; Kaplan, J; Katsanis, N; Etchevers, HC; Faguer, S; Calvas, P
MLA Citation
Chassaing, Nicolas, et al. “Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network..” Genome Res, vol. 26, no. 4, Apr. 2016, pp. 474–85. Pubmed, doi:10.1101/gr.196048.115.
URI
https://scholars.duke.edu/individual/pub1121355
PMID
26893459
Source
pubmed
Published In
Genome Res
Volume
26
Published Date
Start Page
474
End Page
485
DOI
10.1101/gr.196048.115

Ectopic Expression of Retrotransposon-Derived PEG11/RTL1 Contributes to the Callipyge Muscular Hypertrophy.

The callipyge phenotype is an ovine muscular hypertrophy characterized by polar overdominance: only heterozygous +Mat/CLPGPat animals receiving the CLPG mutation from their father express the phenotype. +Mat/CLPGPat animals are characterized by postnatal, ectopic expression of Delta-like 1 homologue (DLK1) and Paternally expressed gene 11/Retrotransposon-like 1 (PEG11/RTL1) proteins in skeletal muscle. We showed previously in transgenic mice that ectopic expression of DLK1 alone induces a muscular hypertrophy, hence demonstrating a role for DLK1 in determining the callipyge hypertrophy. We herein describe newly generated transgenic mice that ectopically express PEG11 in skeletal muscle, and show that they also exhibit a muscular hypertrophy phenotype. Our data suggest that both DLK1 and PEG11 act together in causing the muscular hypertrophy of callipyge sheep.
Authors
Xu, X; Ectors, F; Davis, EE; Pirottin, D; Cheng, H; Farnir, F; Hadfield, T; Cockett, N; Charlier, C; Georges, M; Takeda, H
MLA Citation
Xu, Xuewen, et al. “Ectopic Expression of Retrotransposon-Derived PEG11/RTL1 Contributes to the Callipyge Muscular Hypertrophy..” Plos One, vol. 10, no. 10, 2015. Pubmed, doi:10.1371/journal.pone.0140594.
URI
https://scholars.duke.edu/individual/pub1111255
PMID
26474044
Source
pubmed
Published In
Plos One
Volume
10
Published Date
Start Page
e0140594
DOI
10.1371/journal.pone.0140594

Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies

Rare single-gene disorders cause chronic disease. However, half of the 6000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole-exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole-exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sibships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy, we detect the causative gene. In six sibships, we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sibships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus, whole-exome resequencing establishes an efficient, noninvasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms. © 2013 International Society of Nephrology.
Authors
Gee, HY; Otto, EA; Hurd, TW; Ashraf, S; Chaki, M; Cluckey, A; Vega-Warner, V; Saisawat, P; Diaz, KA; Fang, H; Kohl, S; Allen, SJ; Airik, R; Zhou, W; Ramaswami, G; Janssen, S; Fu, C; Innis, JL; Weber, S; Vester, U; Davis, EE; Katsanis, N; Fathy, HM; Jeck, N; Klaus, G; Nayir, A; Rahim, KA; Attrach, IA; Hassoun, IA; Ozturk, S; Drozdz, D; Helmchen, U; O'toole, JF; Attanasio, M; Lewis, RA; Nürnberg, G; Nürnberg, P; Washburn, J; Macdonald, J; Innis, JW; Levy, S; Hildebrandt, F
MLA Citation
Gee, H. Y., et al. “Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies.” Kidney International, vol. 85, no. 4, Jan. 2014, pp. 880–87. Scopus, doi:10.1038/ki.2013.450.
URI
https://scholars.duke.edu/individual/pub1028407
Source
scopus
Published In
Kidney International
Volume
85
Published Date
Start Page
880
End Page
887
DOI
10.1038/ki.2013.450

KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes.

KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies.
Authors
Putoux, A; Thomas, S; Coene, KLM; Davis, EE; Alanay, Y; Ogur, G; Uz, E; Buzas, D; Gomes, C; Patrier, S; Bennett, CL; Elkhartoufi, N; Frison, M-HS; Rigonnot, L; Joyé, N; Pruvost, S; Utine, GE; Boduroglu, K; Nitschke, P; Fertitta, L; Thauvin-Robinet, C; Munnich, A; Cormier-Daire, V; Hennekam, R; Colin, E; Akarsu, NA; Bole-Feysot, C; Cagnard, N; Schmitt, A; Goudin, N; Lyonnet, S; Encha-Razavi, F; Siffroi, J-P; Winey, M; Katsanis, N; Gonzales, M; Vekemans, M; Beales, PL; Attié-Bitach, T
MLA Citation
Putoux, Audrey, et al. “KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes..” Nat Genet, vol. 43, no. 6, June 2011, pp. 601–06. Pubmed, doi:10.1038/ng.826.
URI
https://scholars.duke.edu/individual/pub767842
PMID
21552264
Source
pubmed
Published In
Nat Genet
Volume
43
Published Date
Start Page
601
End Page
606
DOI
10.1038/ng.826

Research Areas:

Abnormalities, Multiple
Adolescent
Alleles
Animals
Animals, Genetically Modified
Antigens, Neoplasm
Axoneme
Bardet-Biedl Syndrome
Base Sequence
Body Patterning
Bone and Bones
Brain
Caenorhabditis elegans
Cardiomyopathies
Cell Line
Cell Polarity
Cells, Cultured
Cerebellar Ataxia
Cerebellar Diseases
Cerebellum
Chaperonins
Child
Chromatography, High Pressure Liquid
Cilia
Ciliary Motility Disorders
Cohort Studies
Conserved Sequence
Craniosynostoses
Cytoskeletal Proteins
DNA Copy Number Variations
DNA Mutational Analysis
DNA, Intergenic
Diagnosis
Disease
Disease Models, Animal
Early Diagnosis
Embryo, Mammalian
Embryo, Nonmammalian
Encephalocele
Epistasis, Genetic
Eukaryota
Evolution, Molecular
Eye Abnormalities
Family Health
Fibroblasts
Gastrulation
Gene Deletion
Gene Duplication
Gene Expression
Gene Expression Profiling
Gene Expression Regulation
Gene Expression Regulation, Developmental
Gene Frequency
Gene Knockdown Techniques
Genes, Dominant
Genes, Helminth
Genes, Recessive
Genes, X-Linked
Genetic Association Studies
Genetic Diseases, Inborn
Genetic Heterogeneity
Genetic Load
Genetic Loci
Genetic Markers
Genetic Predisposition to Disease
Genetic Testing
Genetic Therapy
Genetic Variation
Genetic Vectors
Genetics, Medical
Genome, Human
Genotype
Green Fluorescent Proteins
HEK293 Cells
Hand Deformities, Congenital
Heart Defects, Congenital
Hedgehog Proteins
Hirschsprung Disease
Homozygote
Human genetics
Humans
Immediate-Early Proteins
Immunohistochemistry
Infant
Inheritance Patterns
Intracellular Signaling Peptides and Proteins
Jaw Abnormalities
Kartagener Syndrome
Kidney
Kidney Diseases, Cystic
Leukoencephalopathies
Mice
Microinjections
Microscopy, Electron, Transmission
Microscopy, Fluorescence
Models, Animal
Molecular Sequence Data
Molecular genetics
Morphogenesis
Multiprotein Complexes
Muscle, Skeletal
Muscular Diseases
Mutation
Mutation, Missense
Myocardium
Neurons, Afferent
Oligonucleotide Array Sequence Analysis
Oligonucleotides, Antisense
Otx Transcription Factors
Pedigree
Penetrance
Phenotype
Photoreceptor Cells
Polymorphism, Single Nucleotide
Proteins
Proteome
Proteomics
RNA
Respiratory System
Retina
Retinal Degeneration
Retinitis Pigmentosa
Ribosomal Proteins
Sequence Alignment
Sequence Analysis, DNA
Sequence Homology, Amino Acid
Signal Transduction
Situs Inversus
Syndrome
Systems Biology
Transcription Factors
Transcription, Genetic
Vertebrates
Wnt Proteins
Zebrafish