LHX4

Gene Facts

• HGNC Symbol: LHX4 (HGNC:21734)
• HGNC Name: LIM homeobox 4
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: Gsh4
• %HI: 6.37
• pLI: 0.57
• LOEUF: 0.59
• Cytoband: 1q25.2
• Genomic Coordinates:

  GRCh37/hg19:	chr1:180199399-180248119
  GRCh38/hg38:	chr1:180228375-180278984

• MANE Select Transcript: NM_033343.4 ENST00000263726.4
• Function: May play a critical role in the development of respiratory control mechanisms and in the normal growth and maturation of the lung. Binds preferentially to methylated DNA (PubMed:28473536). {ECO:0000250, ECO:0000269|PubMed:28473536}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-21594
• ClinGen Curation ID: CCID:007401
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Little Evidence for Haploinsufficiency (1)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 04/25/2022

Haploinsufficiency (HI) Score Details

• HI Score: 1
• HI Evidence Strength: Little Evidence for Haploinsufficiency

HI Disease

• short stature-pituitary and cerebellar defects-small sella turcica syndrome

HI Evidence

• PUBMED: 11567216
  Machinis et al. (2001) reported a splicing variant in the intron preceding exon 5 of LHX4, c.607-1G>C, in four individuals exhibiting short stature and defects in the sella turcica. This splicing variant segregates in a dominant and fully penetrant manner, but variable phenotype over three generations. This family was followed up in a later study; the clinical phenotype described was consistent with that of CPHD (Combined pituitary hormone deficiency) (Castinetti F et al., 2008. PMID: 18445675). This study confirmed the lack of stimulatory effects of mutant LHX4 (intron 4 c.607–1 G>C) relative to wild-type LHX4 on GH promoter and indirectly on POU1F1 promoter.
• PUBMED: 18445675
  Castinetti et al. (2008) reported a novel loss of function variant, c.293_294 InsC (p.Thr99fs), in LHX4 from a father and two brothers with congenital hypopituitarism. Two brothers presented somato-lactotroph and thyrotroph deficiencies, with pituitary hypoplasia and poorly developed sella turcica; the youngest brother (propositus) also had corpus callosum hypoplasia and ectopic neurohypophysis; their father only had somatotroph deficiency and delayed puberty with pituitary hyperplasia. Functional studies showed that the variant induced a complete loss of transcriptional activity on POU1F1 promoter and a lack of DNA binding. Cotransfection of p.Thr99fs mutant and wild-type LHX4 failed to evidence any dominant negative effect, suggesting a mechanism of haploinsufficiency. It is predicted to be a frameshift (p.Thr99 frameshift) in the second LIM region with a stop codon occurring 53 amino acids after codon 99 (p.Thr99AsnfsX53). The mother did not carry the variant. No other family member was available for genetic studies. Patients bearing the heterozygous p.Thr99fs variant had variable phenotypes.
• PUBMED: 23029363
  Takagi et al. (2012) reported an individual with a c.249-1G>A variant in the LHX4 gene who was diagnosed as having isolated GHD at 5 yr of age. Although this patient did not show episodes of adrenal insufficiency, longitudinal follow-up showed that her peak blood cortisol and plasma ACTH levels after insulin tolerance test decreased gradually with age. The other patient with p. V75I showed GH, TSH, and gonadotropin deficiency. Both variants were also identified in apparently normal father and siblings.
• PUBMED: 25955177
  Rochette et al. (2015) reported two heterozygous loss of function variants, W204X and delLys242, and 2 new missense variants, N271S and Q346R, in patients with congenital hypopituitarism by Sanger sequencing of the LHX4 gene. The W204X variant was associated with early GH and TSH deficiencies and later onset ACTH deficiency. No genetic analysis could be performed on clinically unaffected parents, older sister and younger brother. The in-frame deletion variant, delLys242, was detected in a boy who was diagnosed at the age of one month because of prolonged jaundice. FSH/LH and testosterone were evaluated at 2 months of age due to the prepubertal age, and presented a normal pattern throughout postnatal gonadotropic surge. This variant was inherited from unaffected mother, who did not have any pituitary deficiency and had normal pituitary MRI. No other family member was available.
• PUBMED: 27820671
  Cohen et al. (2017) reported three loss of function variants, p.(Tyr131*), p.(Arg48Thrfs*104), c.606+1G>T, and 4 missense variants, p.Arg65Val, p.Thr163Pro, p.Arg221Gln, and p.Arg235Gln, in 7 families presenting a congenital hypopituitarism. These variants were identified by Sanger sequencing of the LHX4 gene (NM_033343). Functional studies showed the p.(Tyr131*), p.(Arg48Thrfs*104), and p.Thr163Pro variants result in a loss of function of the recombinant proteins which lose their ability to transactivate at least 3 target promoters (POU1F1, GH, and PRL). The c.606+1G>T is an unambiguous splice defect, and destructs the invariant GT sequence of the splice donor site of intron 4. Both healthy parents are negative for this variant. The p.(Tyr131*) is inherited from unaffected mother, while the p.(Arg48Thrfs*104), is inherited from unaffected father. They concluded that LHX4 variants were found to be associated with variable expressivity, and most of them with incomplete penetrance.

• HI Evidence Comments: While variants within LHX4 have been observed in individuals with short stature and pituitary hormone deficiency, it is unclear at this time the role haploinsufficiency plays in disease mechanism. Large deletions overlapping this gene (in addition to several other genes) have reported short stature as a phenotype (PMID:20534763), but several putative loss of function variants have been reported in both affected and unaffected individuals. Pituitary hormone deficiency is common to all patients with variability in cerebellar or cranial structural anomalies. Pathogenic variant in LHX4 is reportedly rare although heterozygous variants in the LHX4 gene (602146) on chromosome 1q25 have been reported in families and individuals with combined pituitary hormone deficiency (262700). Affected individuals with various type of variants in LHX4 gene present short statue, defective sella turcica and reduction in TSH, LH, FSH, or ACTH associated with variable expressivity and incomplete penetrance (Hemwong N et al., 2020. PMID: 32071780). Several in vitro studies have shown that mutants did not have a dominant negative effect. Other relevant information includes: Tajima et al. (2007) (PMID:17527005) describes a novel missense variant (P366T) in exon 6 of the LHX4 gene in a Japanese patient who presented a severe combined pituitary hormone deficiency with pituitary hypoplasia, ectopic posterior lobe and a poorly developed sella turcica. This patient has deficiencies of GH, prolactin, TSH, LH, FSH, ACTH, a hypoplastic anterior lobe, an ectopic posterior pituitary, a poorly developed sella turcica, Chiari malformation, and respiratory distress syndrome. Neither of the patient's parents harbored this variant. Pfaeffle et al. (2008) (PMID 18073311) report three heterozygous missense variants, R84C, L190R and A210P in the LHX4 gene. The patients have GH deficiency; some also display reductions in TSH, LH, FSH, or ACTH, and aberrant pituitary morphology. Structural models predict that the aberrant L190R and A210P LHX4 proteins would have impaired DNA binding and gene activation properties. Consistent with these models, EMSAs and transfection experiments using pituitary gene promoters demonstrate that whereas the R84C form has reduced activity, the L190R and A210P proteins are inactive. Tajima et al. (2013) (PMID 23990694) reported two missense variants (p.P389T and p.V101A) of LHX4 in two Japanese patients with CPHD. One patient with P389T showed severe respiratory distress and hypoglycemia soon after birth and had defects of all anterior pituitary hormones. These symptoms were improved by hormone replacement. MRI demonstrated a hypoplastic anterior pituitary, ectopic posterior lobe and a poorly developed sella turcica. The second patient with p.V101A in the LIM domain in exon 3 also had a small anterior pituitary and ectopic posterior lobe but had a normal sized sella turcica. In vitro functional analysis demonstrated that this mutation could not activate the POU1F1 and FSHβ subunit gene promoter. Gucev et al. (2016) (PMID 27464418) reported a missense variant, c.250C>T (R84C) in LHX4, in a 14 year old boy presenting with short stature, convergent strabismus and nystagmus. This variant is inherited from his healthy father. Dateki et al. (2010) (PMID 20534763) reported the first patient with a de novo 0.5 Mb heterozygous deletion including the LHS4 gene and additional three genes, CEP350, QSOX1 and ACBD6. This patient had a small anterior pituitary, ectopic posterior lobe and underdeveloped sella turcica. Whereas GH, TSH, LH and FSH were deficient, ACTH secretion was retained when he was evaluated at the age of 17 yr.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity