GHR – Laron syndrome

Laron syndrome is a rare autosomal recessive growth hormone (GH) insensitivity disorder caused by biallelic mutations in the growth hormone receptor gene (GHR) (Gene Symbol; Disease Name). Affected individuals present with severe postnatal growth failure, characteristic craniofacial features, and biochemical evidence of high circulating GH but low IGF-I and GH binding protein (GHBP).

Extensive case series report over 400 unrelated patients harboring more than 100 distinct GHR variants, including nonsense, missense, splice-site, frameshift, intronic pseudoexon activation, and large deletions. Mutations localize throughout the extracellular, transmembrane, and intracellular domains, with geographic founder effects (e.g., E180splice in Ecuadorians) and private alleles in consanguineous families ([PMID:8488849]; [PMID:1284474]).

Segregation analysis in multiple consanguineous pedigrees demonstrates recessive inheritance, with homozygous or compound heterozygous variants co-segregating with the phenotype in siblings and extended relatives (e.g., three affected siblings in a Pakistani family and seven relatives with intragenic deletions in a Chinese pedigree) ([PMID:37780997]; [PMID:25196842]).

The variant spectrum encompasses 34 nonsense mutations (e.g., c.1A>T (p.Met1Leu) abolishing the initiation codon) and over 20 missense changes that disrupt receptor folding or ligand binding. Recurrent hotspot mutations include R43X and D152H, with intronic mutations such as c.618+792A>G activating a pseudoexon and causing aberrant splicing ([PMID:9258809]; [PMID:12199334]; [PMID:11468686]).

Functional studies confirm loss of cell-surface receptor expression, impaired GH binding, defective STAT5 activation, and dominant-negative effects of truncated isoforms. In vitro assays with HEK293 or COS-1 cells show mutant receptors retained in the endoplasmic reticulum, failure of GHBP release, and abrogated JAK2/STAT5 signaling, consistent across multiple alleles (Phe96Ser, D152H, S226I) ([PMID:1719554]; [PMID:8137822]; [PMID:14678285]).

Integration of genetic and experimental data meets ClinGen criteria for a Definitive gene–disease relationship. GHR molecular testing is essential for the accurate diagnosis of Laron syndrome, carrier detection, prenatal/preimplantation genetic diagnosis, and guides recombinant IGF-I therapy.

Key Take-home: Comprehensive GHR variant analysis is critical for diagnosing GH insensitivity and optimizing management in Laron syndrome.

References

• Journal of endocrinological investigation • 1997 • A homozygous nonsense mutation of the human growth hormone receptor gene in a Sardinian boy with Laron-type dwarfism. PMID:9258809
• American journal of human genetics • 1993 • Diverse growth hormone receptor gene mutations in Laron syndrome. PMID:8488849
• Human mutation • 1992 • Mutation creating a new splice site in the growth hormone receptor genes of 37 Ecuadorean patients with Laron syndrome. PMID:1284474
• 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 EMBO journal • 1994 • A single amino acid substitution in the exoplasmic domain of the human growth hormone (GH) receptor confers familial GH resistance (Laron syndrome) with positive GH-binding activity by abolishing receptor homodimerization. PMID:8137822

Evidence Based Scoring (AI generated)