TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci

Abstract

<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>

The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency

“…Further, a bioinformatic screening revealed STUB1, a gene previously associated with CHH, as a putative TCF12 interactor gene. The overexpression of stub1 in tcf12 mutant zebrafish is able to restore the GnRH neuron phenotype, strongly supporting the role of TCF12 in the GnRH system [194]. 4.2.14.…”

“…Early expression studies in mouse embryos showed a strong expression of Tcf12 transcript in neurogenic areas [195] and Tcf12-null mice developed exencephaly with a high percentage of postnatal death [196]. Thus, alternative functional experiments in zebrafish demonstrated that loss of tcf12 reduced the axonal length of the terminal nerve and impaired GnRH neuron patterning [194]. Further, a bioinformatic screening revealed STUB1, a gene previously associated with CHH, as a putative TCF12 interactor gene.…”

“…TCF12 (chr 15q21.3) is a member of the basic helix-loop-helix (bHLH) transcription factors subfamily and TCF12 haploinsufficiency causes premature cranial suture fusion, leading to a rare developmental disorder known as craniosynostosis [193]. A recent report highlighted the presence of TCF12 variants in 13 individuals from 12 KS pedigrees, with few cases also presenting with craniosynostosis, implicating a possible genotype-phenotype correlation [194].…”

An integrated analysis of mRNAs and lncRNAs in goat's hypothalamus to explore the onset of puberty

“…In the present study, TCF12, STAT1, STAT2, GATA3 and TEAD4 were significantly enriched by analysis of transcription factor binding sites. TCF12 was involved in GnRH and associated with litter size in pigs (Davis et al, 2020; Tao et al, 2013). STAT signalling was discovered by suppression of subtractive hybridization, associated with precocious puberty in goat hypothalamus and pituitary tissues (Cao et al, 2015; Liu et al, 2021).…”

Neurodevelopmental, Cognitive, and Psychosocial Outcomes for Individuals With Pathogenic Variants in the TCF12 Gene and Associated Craniosynostosis

“…Of interest is a recent report that pathogenic TCF12 variants similar or identical to those causing CS may alternatively be associated with an apparently distinct neurodevelopmental disorder, Kallmann syndrome [gonadotrophin-releasing hormone (GnRH) deficiency associated with anosmia]. 33 This highlights a role for TCF12 in the function of GnRH neurons, with the secretion of GnRH being central to normal activity of the hypothalamicpituitary-gonadal axis. The mechanism(s) to explain the different clinical presentations associated with similar or identical TCF12 variants are currently unknown and require further investigation.…”