PUBLICATION
TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci
- Authors
- Davis, E.E., Balasubramanian, R., Kupchinsky, Z.A., Keefe, D.L., Plummer, L., Khan, K., Meczekalski, B., Heath, K.E., Lopez-Gonzalez, V., Ballesta-Martinez, M.J., Margabanthu, G., Price, S., Greening, J., Brauner, R., Valenzuela, I., Cusco, I., Fernandez-Alvarez, P., Wierman, M.E., Li, T., Lage, K., Barroso, P.S., Chan, Y.M., Crowley, W.F., Katsanis, N.
- ID
- ZDB-PUB-200706-3
- Date
- 2020
- Source
- Human molecular genetics 29(14): 2435-2450 (Journal)
- Registered Authors
- Davis, Erica, Katsanis, Nicholas
- Keywords
- none
- MeSH Terms
-
- Adult
- Aged
- Animals
- Basic Helix-Loop-Helix Transcription Factors/genetics*
- Disease Models, Animal
- Female
- Genes, Dominant/genetics
- Gonadotropin-Releasing Hormone/deficiency
- Gonadotropin-Releasing Hormone/genetics*
- Haploinsufficiency/genetics
- Humans
- Kallmann Syndrome/genetics*
- Kallmann Syndrome/pathology
- Male
- Middle Aged
- Mutation/genetics
- Neurons/metabolism
- Neurons/pathology
- Phenotype
- Ubiquitin-Protein Ligases/genetics*
- Zebrafish/genetics
- Zebrafish Proteins/genetics*
- PubMed
- 32620954 Full text @ Hum. Mol. Genet.
Citation
Davis, E.E., Balasubramanian, R., Kupchinsky, Z.A., Keefe, D.L., Plummer, L., Khan, K., Meczekalski, B., Heath, K.E., Lopez-Gonzalez, V., Ballesta-Martinez, M.J., Margabanthu, G., Price, S., Greening, J., Brauner, R., Valenzuela, I., Cusco, I., Fernandez-Alvarez, P., Wierman, M.E., Li, T., Lage, K., Barroso, P.S., Chan, Y.M., Crowley, W.F., Katsanis, N. (2020) TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci. Human molecular genetics. 29(14):2435-2450.
Abstract
Dysfunction of the gonadotropin-releasing hormone (GnRH) axis causes a range of reproductive phenotypes resulting from defects in the specification, migration and/or function of GnRH neurons. To identify additional molecular components of this system, we initiated a systematic genetic interrogation of families with isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD). Here we report thirteen families (twelve autosomal dominant, and one autosomal recessive) with an anosmic form of IGD (Kallmann syndrome; KS) with loss-of-function mutations in TCF12, a locus also known to cause syndromic and non-syndromic craniosynostosis. We show that loss of tcf12 in zebrafish larvae perturbs GnRH neuronal patterning with concomitant attenuation of the orthologous expression of tcf3a/b, encoding a binding partner of TCF12; and stub1, a gene that is both mutated in other syndromic forms of IGD and maps to a TCF12 affinity network. Finally, we report that restored STUB1 mRNA rescues loss of tcf12 in vivo. Our data extend the mutational landscape of IGD; highlight the genetic links between craniofacial patterning and GnRH dysfunction; and begin to assemble the functional network that regulates the development of the GnRH axis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping