Alternative titles; symbols
HGNC Approved Gene Symbol: LHX3
Cytogenetic location: 9q34.3 Genomic coordinates (GRCh38): 9:136,196,250-136,205,128 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.3 | Pituitary hormone deficiency, combined, 3 | 221750 | Autosomal recessive | 3 |
Zhadanov et al. (1995) cloned and sequenced mouse Lhx3 cDNA based on its homology to the gene in Xenopus laevis. The predicted protein contains 2 tandemly repeated LIM domains and a homeodomain. Alternative splicing generates 2 different mRNAs that specify the proteins Lhx3a and Lhx3b, which are 400 and 402 amino acids long, respectively. Zhadanov et al. (1995) noted that the LIM motif, named after the 3 homeodomain proteins lin-11 (Freyd et al., 1990), Islet-1 (ISL1; 600366), and mec-3 (Way and Chalfie, 1988), is a zinc-binding motif composed of 50 to 60 amino acid residues that contain a conserved pattern of cysteine and histidine residues that form a pair of zinc fingers separated by a linker of 2 amino acids.
Sloop et al. (1999) identified 2 isoforms of human LHX3, LHX3a and LHX3b, which differ in their ability to trans-activate pituitary gene targets. These factors are identical within the LIM domains and the homeodomain, but differ in their amino-terminal sequences preceding the LIM motifs. Both isoforms are localized to the nucleus and are expressed in the adult human pituitary, but gene activation studies demonstrated characteristic functional differences.
Netchine et al. (2000) found that the human and mouse LHX3 proteins share 94% sequence identity.
Using in situ hybridization of human embryonic and fetal tissue, Rajab et al. (2008) detected expression of LHX3 in the developing anterior pituitary and in defined regions of the sensory epithelium of the developing inner ear in a pattern overlapping that of SOX2 (184429).
Zhadanov et al. (1995) found that the Lhx3 gene in the mouse contains 6 exons. The first LIM domain is encoded by exon 2 and the second by exon 3. The homeobox is shared by exons 4 and 5.
Netchine et al. (2000) determined that the human LHX3 gene contains at least 6 exons and spans a genomic fragment of at least 6 kb.
Sloop et al. (2000) mapped the human LHX3 gene to the subtelomeric region of chromosome 9 at band 9q34.3, within a region noted for chromosomal translocation and insertion events. Netchine et al. (2000) also mapped the LHX3 gene to 9q34 by screening of a panel of 24 hybrid somatic cell lines by PCR and further localization using fluorescence in situ hybridization.
By interspecific backcross analysis, Zhadanov et al. (1995) mapped the Lhx3 gene to the proximal region of mouse chromosome 2, in a region that shares homology with human chromosomes 9q and 10p. Particularly tight linkage was found between Lhx3 and Notch1 (190198) in the mouse. Mbikay et al. (1995) also mapped the Lhx3 gene to mouse chromosome 2.
Tsuchida et al. (1994) found that the combinatorial expression of 4 LIM genes, Isl1 (600366), Isl2 (609481), Lim1 (LHX1; 601999), and Lim3, in the developing embryonic chicken defined subclasses of motor neurons that segregated into columns in the spinal cord and selected distinct axonal pathways. These genes were expressed prior to the formation of distinct motor axon pathways and before motor columns appeared.
Zhadanov et al. (1995) found that Lhx3 mRNA accumulates in the Rathke pouch, the primordium of the pituitary, at day 9.5 of mouse embryonic development and is detected predominantly in the anterior and intermediate lobes of the adult pituitary. This suggested that the gene product may be involved in the establishment and maintenance of the differentiated phenotype of pituitary cells. Additional functions were suggested by the fact that Lhx3 is also expressed bilaterally along the spinal cord and the hindbrain at early stages of development.
Sloop et al. (1999) showed that LHX3a trans-activated the alpha-glycoprotein subunit (CGA; 118850) promoter and a reporter construct containing a high-affinity LHX3 binding site more effectively than the LHX3b isoform. In addition, LHX3a synergized with the pituitary POU domain factor, PIT1 (173110), to strongly induce transcription of the TSH beta-subunit gene (188540), while LHX3b did not. The authors concluded that the differences in gene activation properties between LHX3a and LHX3b correlate with their DNA binding to sites within these genes. The short LHX3b-specific amino-terminal domain inhibits DNA binding and gene activation functions of the molecule. These data suggested that isoforms of LHX3 may play distinct roles during development of the mammalian pituitary gland and other neuroendocrine systems.
Many lines of evidence indicate that genetically distinct subtypes of motor neurons are specified during development, with each type having characteristic properties of axon guidance and cell body migration. Motor neuron subtypes express unique combinations of LIM-type homeodomain factors that are thought to act as intrinsic genetic regulators of the cytoskeletal events that mediate cell migration, axon navigation, or both. Although experimentally displaced motor neurons can pioneer new routes to their targets, in many cases the axons of motor neurons in complete isolation from their normal territories passively follow stereotypical pathways dictated by the environment. To investigate the nonspecific versus genetically controlled regulation of motor connectivity, Sharma et al. (2000) forced all motor neurons to express ectopically a LIM gene combination appropriate for the subgroup that innervates axial muscles, in particular, LHX3. Sharma et al. (2000) demonstrated that this genetic alteration is sufficient to convert the cell body settling pattern, gene expression profile, and axonal projections of all motor neurons to that of the axial subclass. Nevertheless, elevated occupancy of the axial pathway can override their genetic program, causing some axons to project to alternative targets.
LHX3 is involved in the generation of 2 adjacent but distinct cell types for locomotion, motor neurons and V2 interneurons. Using in vivo function and protein interaction assays, Thaler et al. (2002) found that LHX3 binds directly to the LIM cofactor NLI (603451) to trigger V2 interneuron differentiation. In motor neurons, however, ISL1 is available to compete for binding to NLI, displacing LHX3 to a high-affinity binding site on the C-terminal region of ISL1 and thereby transforming LHX3 from an interneuron-promoting factor to a motor neuron-promoting factor. This switching mechanism enables specific LIM complexes to form in each cell type and ensures that neuronal fates are tightly segregated.
Lee and Pfaff (2003) showed that Neurod4 (611635) and Ngn2 (NEUROG2; 606624) actively participated with Isl1 and Lhx3 to specify motor neuron subtype in embryonic chicken spinal cord and in P19 mouse stem cells.
After observing expression of LHX3 in a pattern overlapping that of SOX2 in the inner ear and pituitary, Rajab et al. (2008) performed transfection studies in CHO cells that demonstrated that SOX2 is capable of binding to and activating transcription of the LHX3 proximal promoter in vitro.
In affected members of 2 unrelated consanguineous families with combined pituitary hormone deficiency (CPHD3; 221750) in whom mutation in the PROP1 gene (601538) had been excluded, Netchine et al. (2000) used a candidate-gene approach developed on the basis of documented pituitary abnormalities of a recessive lethal mutation in mice generated by targeted disruption of Lhx3 (Sheng et al., 1996) and identified homozygosity for a nonsense mutation and an intragenic deletion in the LHX3 gene (600577.0001 and 600577.0002, respectively). Affected individuals from both families had deficiency of all anterior pituitary hormones except ACTH and also displayed rigidity of the cervical spine. The data were considered consistent with function of LHX3 in the proper development of all anterior pituitary cell types, except corticotropes, and of extrapituitary structures as well.
In a 6.75-year-old boy with CPHD and rigid cervical spine, Bhangoo et al. (2006) identified homozygosity for a 1-bp deletion mutation in the LHX3 gene (600577.0003).
Sloop et al. (2000) studied 9 children with CPHD or isolated GH deficiency, all with abnormal pituitary gland development featuring ectopic posterior lobe location and frequently hypoplastic anterior lobes. No loss-of-function mutations in the LHX3 gene were detected.
Pfaeffle et al. (2007) identified 7 subjects in 4 families (1.9%) with LHX3 mutations (600577.0004-600577.0007) from 366 patients with pituitary insufficiency representing 342 pedigrees. None of the 48 patients with isolated GH deficiency had an LHX3 mutation. The authors concluded that LHX3 mutations are a rare cause of CPHD and that limited neck rotation is not a universal feature, since it was not observed in the 3 affected sibs from 1 mutation-positive family (600577.0007).
Rajab et al. (2008) sequenced the LHX3 gene in 4 patients from 2 unrelated consanguineous families, who presented with early-onset hypopituitarism with neonatal hypoglycemia, short neck with limited rotation, and mild sensorineural hearing loss, and identified homozygosity for a large intragenic deletion (600577.0008) and a nonsense mutation (600577.0009), respectively. Rajab et al. (2008) noted that the phenotypes of these patients included some features not previously associated with mutation in LHX3, including ACTH deficiency and sensorineural hearing loss. The 3 affected members of the family with the deletion also exhibited skin laxity and skeletal abnormalities; the authors suggested that a second recessive mutation might be segregating in that family.
A mouse recessive mutation called 'stubby' (stb) maps to the same area on chromosome 2 as the Lhx3 gene (Mbikay et al., 1995). Homozygous stb mice exhibit disproportionate dwarfing, manifested in shorter than normal head, body, and legs. Whereas stb/stb females are fertile, males are not. Considering the preferential expression of lim3 in the pituitary, its ability to transactivate the pituitary genes, and the importance of this gland for regulating growth and fertility, the authors suggested that Lhx3 is a good candidate gene for the small stb mutation.
Sheng et al. (1996) used targeted disruption of the Lhx3 gene in mice to analyze growth and differentiation of the Rathke pouch and pituitary cell lineages. Mice heterozygous for the mutation were apparently normal and fertile, whereas homozygous embryos were stillborn or died within 24 hours after birth. The hindbrain, spinal cord, and pineal gland were grossly normal; the posterior lobe of the pituitary appeared normal, but the anterior and intermediate lobes of the pituitary were absent. Although some Lhx3 -/- pouch cells were able to differentiate and express POMC (176830), a marker for corticotroph lineage, these cells failed to proliferate. The adrenal cortex was hypoplastic, secondary to pituitary hormone deficits. Sheng et al. (1996) noted that the Lhx3 -/- mice provide a genetic paradigm for study of pituitary development and the ontogeny of the hypothalamic-pituitary axis.
Sharma et al. (1998) defined the expression of 2 related genes, Lhx3 and Lhx4, during motor neuron development, using CRE-mediated lineage tracing in the mouse. They found that these factors have an extremely dynamic expression pattern. For a brief period, as motor neurons are born, Lhx3 and Lhx4 are expressed in all motor neuron classes that extend axons ventrally from the neural tube (v-MNs). In contrast, motor neurons that send axons dorsally from the neural tube (d-MNs) arise from cells that do not express Lhx3 and Lhx4 as they are born. Following v-MN birth, Lhx3 and Lhx4 become restricted to a single motor column. To test whether these LIM-homeodomain factors specify v-MN or motor column identity, Sharma et al. (1998) examined Lhx3 -/-, Lhx4 -/-, and Lhx3 -/- and Lhx4 -/- (double mutant, DKO) knockout mice. In DKO mice, motor neuron differentiation proceeded; however, v-MN cells acquire properties of d-MNs, i.e., they switch their subclass identity to become motor neurons that extend axons dorsally from the neural tube. Moreover, elimination of Lhx3 or Lhx4 alone did not produce this phenotype, indicating that these factors have similar activities in motor neurons. Sharma et al. (1998) also showed that Lhx3 is sufficient to specify v-MN identity when misexpressed in progenitors for d-MN cells. These studies demonstrated that Lhx3 and Lhx4 act independently from the factors that trigger motor neuron differentiation to control the choice of motor neuron axon exit point from the neural tube.
In 3 sibs in a consanguineous family with combined pituitary hormone deficiency with rigid cervical spine (CPHD3; 221750), Netchine et al. (2000) identified a homozygous 347A-G transition in exon 3 of the LHX3 gene, resulting in a tyr116-to-cys (Y116C) substitution at a phylogenetically conserved residue in the LIM2 domain. The unaffected mother and 2 unaffected sibs were heterozygous for the mutation, which was not found in 30 unrelated controls. Severe hypoplasia of the anterior pituitary gland was documented by MRI in 2 of the affected sibs. Rajab et al. (2008) reevaluated 2 of the sibs originally reported by Netchine et al. (2000) and found that they had mild and moderate hearing loss, respectively.
In a 19-year-old man, born of consanguineous parents, who had combined pituitary hormone deficiency and a rigid cervical spine (CPHD3; 221750), Netchine et al. (2000) identified a 23-bp deletion (467del23) in the LHX3 gene, involving the last 3 bases of exon 3 (codons 156 and 157) and the adjacent splice-donor site, and predicted to cause a severely truncated protein lacking the entire homeodomain. The unaffected parents were heterozygous for the deletion, which was not found in 30 unrelated controls. The patient had an enlarged anterior pituitary by MRI that was not documented on a CT scan performed 10 years earlier. Rajab et al. (2008) reevaluated this patient, who had extreme mental retardation, and diagnosed complete deafness on the basis of the absence of any acoustic evoked potential (AEP).
In a 6-year-old boy with combined pituitary hormone deficiency with rigid cervical spine (CPHD3; 221750), Bhangoo et al. (2006) identified homozygosity for a 1-bp deletion (159delT) in exon 2 of the LHX3 gene. The mutation causes a frameshift that is predicted to result in the production of short, inactive LHX3 proteins. The clinically unaffected parents, who had normal anterior pituitary hormone profiles, were both heterozygous for the mutation.
In 2 sibs with combined pituitary hormone deficiency and limited neck rotation (CPHD3; 221750), born of consanguineous Indian parents, Pfaeffle et al. (2007) identified homozygosity for a 629C-T transition of the LHX3 gene (LHX3a), causing an ala210-to-val (A210V) substitution. The mutation was associated with diminished DNA binding and pituitary gene activation, consistent with observed hormone deficiencies. The healthy parents and an unaffected brother were heterozygous for the mutation.
In a boy with combined pituitary hormone deficiency and limited neck rotation (CPHD3; 221750), born of consanguineous Moroccan parents, Pfaeffle et al. (2007) identified homozygosity for a complex mutation in exon 3 of the LHX3 gene in which the GC bases at position 287/288 of the LHX3a ORF were deleted and replaced by a 4-bp insertion (TCCT). The mutation shifts the ORF starting from codon 72, resulting in the introduction of 77 incorrect amino acids and a premature stop codon at position 173 (E173X). The mutation was associated with diminished DNA binding and pituitary gene activation, consistent with observed hormone deficiencies. The parents were heterozygous for the mutation.
In a boy with combined pituitary hormone deficiency and limited neck rotation (CPHD3; 221750), born of consanguineous Algerian parents, Pfaeffle et al. (2007) identified homozygosity for a complete LHX3 deletion. The mutation was associated with diminished DNA binding and pituitary gene activation, consistent with observed hormone deficiencies. Both parents displayed only 1 detectable allele.
In 3 sibs with combined pituitary hormone deficiency (CPHD3; 221750), born of consanguineous Lebanese parents, Pfaeffle et al. (2007) identified homozygosity for a 672G-A transition in exon 5 of the LHX3 gene (LHX3a), resulting in a premature stop at position 224 (trp224-to-ter; W224X) and loss of the carboxyl terminus. The mutation was associated with diminished DNA binding and pituitary gene activation, consistent with observed hormone deficiencies. Four of 6 unaffected sibs and the parents were heterozygous for the mutation. No limitation of neck rotation was observed in the 3 affected sibs.
In 3 affected individuals from a consanguineous family, who had early-onset hypopituitarism with neonatal hypoglycemia, short neck with limited rotation, and mild sensorineural hearing loss (CPHD3; 221750), Rajab et al. (2008) identified homozygosity for a 3,088-bp deletion in the LHX3 gene (c.80532_775+454del3088), resulting in complete loss of exons 2 through 5. The unaffected parents and sibs were all heterozygous for the deletion. The 3 affected sibs also exhibited skin laxity and skeletal abnormalities; the authors suggested that a second recessive mutation might be segregating in that family.
In a boy born of consanguineous parents, who was diagnosed in infancy with combined pituitary hormone deficiency (CPHD3; 221750) with pituitary hypoplasia by MRI, Rajab et al. (2008) identified homozygosity for a 267A-T transversion in exon 2 of the LHX3 gene, resulting in a lys50-to-ter (K50X) substitution. Both unaffected parents were heterozygous carries of the mutation. The patient subsequently developed the appearance of skeletal dysplasia with a short neck, stiff back, and thoracic kyphosis, and audiologic assessment revealed profound (96 dB) sensorineural hearing loss bilaterally. ACTH stimulation unequivocally confirmed a diagnosis of ACTH deficiency in this patient.
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