Lessons from the genetics of laron syndrome

Area of Science:

• Endocrinology
• Human Genetics
• Molecular Biology

Background:

• The growth hormone receptor (GHR) and its circulating binding protein (GHBP) were cloned and sequenced a decade ago.
• The GHBP is structurally identical to the extracellular domain of the GHR.
• Since then, 34 mutations in the GHR gene have been identified.

Purpose of the Study:

• To review and classify the known mutations in the growth hormone receptor (GHR).
• To analyze the genetic defects in patients with Laron syndrome, particularly the Ecuadorian cohort.
• To reconsider the classification of growth hormone insensitivity (GHI) based on new genetic and physiological understanding.

Main Methods:

• Literature review of GHR mutations described in the past decade.
• Analysis of mutation types: deletion, nonsense, missense, frameshift, and splice mutations.
• Examination of genotype-phenotype correlations in Laron syndrome patients.

Main Results:

• A total of 34 GHR mutations have been identified, including various types.
• A single splice mutation in the GHR gene is prevalent in over half of the identified Ecuadorian Laron syndrome patients.
• Variable expression of GHR defects is observed, comparable to variations within genetically homogeneous populations.

Conclusions:

• The Ecuadorian cohort represents a significant portion of identified Laron syndrome cases due to a shared splice mutation.
• Certain features like birth size and intelligence appear unaffected by GHR defects.
• A comprehensive understanding of the GH-GHR-IGF-I axis necessitates revising the classification of GH insensitivity (GHI).