Identifying the Deleterious Effect of Rare LHX4 Allelic Variants, a Challenging Issue

Area of Science:

• Genetics
• Endocrinology
• Molecular Biology

Background:

• * Combined pituitary hormone deficiency (CPHD) is a rare genetic disorder affecting pituitary gland development.
• * Mutations in the LHX4 gene, a key transcription factor in pituitary ontogenesis, have been linked to CPHD.
• * Eight heterozygous LHX4 mutations are previously reported to cause CPHD in humans.

Observation:

• * Four novel heterozygous LHX4 variants (W204X, delK242, N271S, Q346R) were identified in patients with congenital hypopituitarism.
• * In vitro studies assessed protein expression, DNA binding, and transactivation capabilities of these variants.
• * The W204X mutation resulted in a truncated, non-functional protein unable to bind DNA or activate target promoters.

Findings:

• * The W204X LHX4 mutation is associated with early GH and TSH deficiencies, and later ACTH deficiency.
• * Unlike W204X, the delK242, N271S, and Q346R variants demonstrated normal DNA binding and promoter activation, suggesting they are polymorphisms.
• * Functional studies are crucial for determining the pathogenicity of rare LHX4 variants.

Implications:

• * This study confirms the causative role of the LHX4 W204X mutation in CPHD.
• * Childhood-onset ACTH deficiency is added to the clinical spectrum of LHX4-related pituitary disorders.
• * The findings underscore the importance of in vitro functional assays for diagnosing genetic causes of hypopituitarism.