Two coexisting heterozygous frameshift mutations in PROP1 are responsible for a different phenotype of combined...

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Childhood-onset combined pituitary hormone deficiency (CPHD) is often linked to mutations in transcription factor genes like PROP1, POU1F1, LHX3, LHX4, and HESX1.
• Mutations can lead to impaired synthesis of growth hormone (GH) and other pituitary hormones, with variable clinical manifestations influenced by mutation impact and environmental factors.

Purpose of the Study:

• To investigate the genetic basis and clinical characteristics of congenital hypopituitarism in two brothers with an uncommon presentation.
• To identify specific genetic alterations in key pituitary development genes and correlate them with the observed phenotype.

Main Methods:

• Genetic sequencing of PROP1, POU1F1, LHX3, LHX4, and HESX1 genes in affected individuals.
• Analysis of identified mutations, including a known mutational hotspot and a novel alteration in the PROP1 gene.
• In silico prediction of the novel p.R112X mutation's effect on protein architecture.

Main Results:

• Compound heterozygosity in the PROP1 gene was identified in both brothers.
• One brother carried a known mutational hotspot (c.150delA, p.R53fsX164), while the other carried a novel mutation (p.R112X) predicted to disrupt the protein.
• The novel p.R112X mutation preserved over 70% of the homeodomain structure, suggesting potential residual protein activity.

Conclusions:

• A compound heterozygous PROP1 mutation explains the congenital hypopituitarism in the studied brothers.
• The novel p.R112X mutation's ability to preserve homeodomain structure may account for the unusual and distinct clinical phenotype observed.
• This finding underscores the critical role of the DNA-binding homeodomain in PROP1 functionality and offers a potential explanation for atypical presentations of CPHD.