GHR – Growth Hormone Insensitivity Syndrome

Growth hormone receptor (GHR) loss-of-function causes growth hormone insensitivity syndrome (GHIS), also known as Laron syndrome, characterized by extreme short stature, elevated circulating GH, and low IGF-I levels. GHIS follows an autosomal recessive inheritance pattern with biallelic GHR mutations impairing receptor binding or signaling. Clinical diagnosis relies on auxological measurements, GH stimulation tests, and biochemical profiling of IGF-I and GH-binding protein (GHBP).

Genetic evidence is robust: a multinational cohort of 82 GHIS patients harbored 16 distinct homozygous GHR mutations, including frameshifts, nonsense, splice-site, and missense variants (PMID:10102073). Five families with partial GHR gene deletions further substantiated autosomal recessive segregation of pathogenic alleles (PMID:11013443). Notable recurrent variants include c.1A>T (p.Met1Leu), abolishing the translation start codon and preventing receptor synthesis (PMID:12199334).

The variant spectrum spans missense changes in the extracellular domain (e.g., p.Ile153Thr), frameshift insertions activating cryptic exons (e.g., c.618+792A>G), intronic splice‐activating mutations (e.g., c.266+83G>T), and large deletions of exons 3–7. Together, over 30 different GHR alleles have been reported in more than 27 families, with no clear genotype–phenotype correlation in height SDS or IGFBP-3 SDS, suggesting modifying genetic or environmental factors (PMID:10102073).

Functional studies confirm a loss-of-function mechanism. In vitro expression of mutant GHR (e.g., p.Phe118Ser) demonstrates absent plasma membrane localization and lack of GH binding (PMID:1719554). Heterozygous splice-site mutants produce truncated receptors that act dominantly to increase GHBP and inhibit STAT5 signaling (PMID:9467570; PMID:10084588). Knock-in mouse models with cytoplasmic domain truncations reveal progressive growth impairment, reduced STAT5 phosphorylation, and male-specific obesity, mirroring human GHIS phenotypes (PMID:15601831).

Conflicting data include a C422F missense variant in the intracellular domain that shows normal STAT5 activation and normal stature in heterozygotes, indicating it is a benign polymorphism rather than a GHIS-causing allele (PMID:10566675).

Integration of genetic and functional data establishes a definitive GHR–GHIS association. Comprehensive mutation screening informs molecular diagnosis, genetic counseling, and eligibility for IGF-I replacement therapy. Future studies on modifier genes may explain phenotypic variability.

Key Take-home: GHR loss-of-function mutations underlie autosomal recessive growth hormone insensitivity syndrome, and molecular diagnosis guides targeted IGF-I therapy.

References

• Acta paediatrica • 1999 • Relationship between phenotype and genotype in growth hormone insensitivity syndrome. PMID:10102073
• Human Mutation • 2000 • Diverse deletions in the growth hormone receptor gene cause growth hormone insensitivity syndrome. PMID:11013443
• Journal of pediatric endocrinology & metabolism • 2002 • Novel mutation involving the translation initiation codon of the growth hormone receptor gene (GHR) in a patient with Laron syndrome. PMID:12199334
• Proceedings of the National Academy of Sciences of the United States of America • 1991 • Defective membrane expression of human growth hormone (GH) receptor causes Laron-type GH insensitivity syndrome. PMID:1719554
• The Journal of clinical endocrinology and metabolism • 1998 • Growth hormone (GH) insensitivity syndrome with high serum GH-binding protein levels caused by a heterozygous splice site mutation of the GH receptor gene producing a lack of intracellular domain. PMID:9467570
• The Journal of clinical endocrinology and metabolism • 1999 • The C422F mutation of the growth hormone receptor gene is not responsible for short stature. PMID:10566675
• Molecular and Cellular Biology • 2005 • In vivo analysis of growth hormone receptor signaling domains and their associated transcripts. PMID:15601831

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