Model of pediatric pituitary hormone deficiency separates the endocrine and neural functions of the LHX3 transcription factor in vivo

Abstract

The etiology of most pediatric hormone deficiency diseases is poorly understood. Children with combined pituitary hormone deficiency (CPHD) have insufficient levels of multiple anterior pituitary hormones causing short stature, metabolic disease, pubertal failure, and often have associated nervous system symptoms. Mutations in developmental regulatory genes required for the specification of the hormone-secreting cell types of the pituitary gland underlie severe forms of CPHD. To better understand these diseases, we have created a unique mouse model of CPHD with a targeted knockin mutation (Lhx3 W227ter), which is a model for the human LHX3 W224ter disease. The LHX3 gene encodes a LIM-homeodomain transcription factor, which has essential roles in pituitary and nervous system development in mammals. The introduced premature termination codon results in deletion of the carboxyl terminal region of the LHX3 protein, which is critical for pituitary gene activation. Mice that lack all LHX3 function do not survive beyond birth. By contrast, the homozygous Lhx3 W227ter mice survive, but display marked dwarfism, thyroid disease, and female infertility. Importantly, the Lhx3 W227ter mice have no apparent nervous system deficits. The Lhx3 W227ter mouse model provides a unique array of hormone deficits and facilitates experimental approaches that are not feasible with human patients. These experiments demonstrate that the carboxyl terminus of the LHX3 transcription factor is not required for viability. More broadly, this study reveals that the in vivo actions of a transcription factor in different tissues are molecularly separable.endocrinology | growth | reproduction | metabolism

A Recessive Mutation Resulting in a Disabling Amino Acid Substitution (T194R) in the LHX3 Homeodomain Causes Combined Pituitary Hormone Deficiency

“…These phenotypes suggest that the LIM domains and homeodomain are required for all LHX3 functions. However, the carboxyl terminus of LHX3 contains an activation domain that is required for pituitary gene activation [32], and patients and mouse models of CPHD with mutations causing specific loss of the carboxyl terminus of the LHX3 protein have pituitary disease but not the limited neck rotation or other nervous system symptoms, demonstrating that the roles in the pituitary and nervous system are molecularly separable [12,17]. …”

“…Mutations that compromise the overall function of the gene or protein and mutations affecting the LIM domains or the homeodomain appear to result in syndromes involving both the endocrine (CPHD) and nervous (limited neck rotation, possible deafness) systems. By contrast, the carboxyl terminus of LHX3 proteins appears to have roles that are limited to pituitary development and function: mutations affecting only this domain in both human patients and engineered animal models are associated with pituitary diseases without any apparent nervous system deficits [12,17]. …”

“…Mice with inactive Lhx3 genes die shortly following birth of presumptive nervous system deficiencies and have poor structural pituitary development with an associated absence of four of the differentiated cell types and only a minimal population of ACTH-producing corticotropes [11]. By contrast, mice lacking only the carboxyl terminus of the protein are viable but have anterior pituitary deficits causing dwarfism, female infertility, and thyroid insufficiency [12]. …”

Genetically Determined Central Hypothyroidism

“…In certain cases limitation of neck rotation and hearing loss are also observed. The latter characteristic could be explained by the fact that LHX3 is located in the sensory epithelium of the developing inner ear [39][40][41][42]. The disorder is inherited as a recessive trait.…”

A novel 29 bp insertion/deletion (indel) variant of the <i>LHX3</i> gene and its influence on growth traits in four sheep breeds of various fecundity

“…LHX3 and LHX4 are important members of the LIM homeobox family, whose characteristics of the encoded protein include a rich cysteine zinc finger structure. These genes are the most important regulatory factors upstream of the pituitary gland, able to transform expression of GH and PRL directly, as well as adjust the expression level of the POU1F1 gene to influence the other regulators (Colvin et al, 2011;Malik and Rhodes, 2014;Seo et al, 2015).…”