Genetic disorders of nuclear receptors

Abstract

Following the first isolation of nuclear receptor (NR) genes, genetic disorders caused by NR gene mutations were initially discovered by a candidate gene approach based on their known roles in endocrine pathways and physiologic processes. Subsequently, the identification of disorders has been informed by phenotypes associated with gene disruption in animal models or by genetic linkage studies. More recently, whole exome sequencing has associated pathogenic genetic variants with unexpected, often multisystem, human phenotypes. To date, defects in 20 of 48 human NR genes have been associated with human disorders, with different mutations mediating phenotypes of varying severity or several distinct conditions being associated with different changes in the same gene. Studies of individuals with deleterious genetic variants can elucidate novel roles of human NRs, validating them as targets for drug development or providing new insights into structure-function relationships. Importantly, human genetic discoveries enable definitive disease diagnosis and can provide opportunities to therapeutically manage affected individuals. Here we review germline changes in human NR genes associated with "monogenic" conditions, including a discussion of the structural basis of mutations that cause distinctive changes in NR function and the molecular mechanisms mediating pathogenesis.

A comprehensive structural and functional analysis of the ligand binding domain of the nuclear receptor superfamily reveals highly conserved signaling motifs and two distinct canonical forms through evolution

“…It should be mentioned that phenotypes that could be attributed to mutations on NRs may not exhibit said mutations on the final protein product. A number of factors could be responsible for this observation, such as epigenetic actions on NR genes, mutations in non-coding regions affecting enhancers, or mutations on NR cofactors (46). An in-depth look into GR mutations confirmed the aforementioned.…”

Transcriptomic analysis of female and male gonads in juvenile snakeskin gourami (Trichopodus pectoralis)

“…Furthermore, in zebrafish, genome editing to generate mutants of genes encoding PIH proteins resulted in abnormal sperm motility 37 . The photoreceptor-specific nuclear receptor (nr2e3) is an orphan nuclear receptor essential for the development and function of photoreceptor cells 42 . The function of nr2e3 was related to testis development 43 .…”

Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children

“…Humans have 48 different NRs with a diverse range of functions and next-generation sequencing approaches are starting to identify novel and sometimes unexpected phenotypes associated with specific NR variants. 31 Recently, we described recurrent missense mutations that specifically target the Arg92 residue of another nuclear receptor, NR5A1 and which are associated with both 46,XX OTDSD and TDSD in multiple individuals. 32 When this mutation is introduced into the XX mouse, it does not result in testis formation.…”