GH1 – Isolated Congenital Growth Hormone Deficiency

Isolated congenital growth hormone deficiency (IGHD; [MONDO:0000050]) is a rare endocrine disorder characterized by severe short stature due to inadequate secretion or action of pituitary‐derived growth hormone (GH). The GH1 gene (Gene:GH1) encodes the 22 kDa GH isoform essential for normal growth and metabolism. Genetic alterations in GH1 include large homozygous deletions causing autosomal recessive IGHD type IA and heterozygous splice‐site or promoter mutations exerting dominant‐negative effects in IGHD type II.

Genetic evidence supporting the GH1–IGHD association comes from multiple cohorts and case reports. Eight patients were homozygous for a 6–7 kb GH1 gene deletion leading to IGHD type IA (PMID:25116472) and seven non‐consanguineous families harbored heterozygous splice‐site mutations causing exon 3 skipping and a dominant negative GH isoform (n=4 families) (PMID:9385381, PMID:24280736). Three consanguineous siblings carried a homozygous promoter variant c.-223C>T that abolished transcription factor binding and reduced GH1 expression (PMID:27252485).

Segregation analysis confirmed GH1 variants in multiple affected relatives across pedigrees, including two siblings and paternal mosaicism for an intron 3 mutation in one family (affected_relatives=9) (PMID:21933221). Recurrent mutations such as c.291+1G>A and c.172-1G>C have been described in diverse populations, indicating mutational hotspots in splice‐junctions of GH1.

The variant spectrum encompasses large deletions (6.7–7.6 kb), splice‐site mutations (e.g., c.291+1G>A leading to exon 3 skipping), promoter changes (c.-223C>T), and missense substitutions such as c.626G>A (p.Arg209His) identified in a multigenerational pedigree with variable GH insensitivity (PMID:31835104).

Functional and experimental studies elucidate GH1 pathogenic mechanisms. In vitro splicing assays demonstrate that splice‐site mutations induce exon 3 skipping, creating a 17.5 kDa GH isoform that dimerizes with wild‐type GH and impairs its secretion (PMID:11836331). Cellular models show that retained misfolded GH triggers endoplasmic reticulum (ER) stress and apoptosis in somatotrophs, further reducing GH output (PMID:23736291). Luciferase reporter assays confirm that promoter variants disrupt Pit-1 or SP1 binding, resulting in decreased GH1 transcription.

Integration of genetic and functional data supports a Definitive gene–disease relationship. Both autosomal recessive loss‐of‐function and autosomal dominant dominant‐negative mechanisms are well documented, with concordant clinical, segregation, and experimental findings. Key take-home: GH1 mutation analysis is critical for diagnosis and genetic counseling in IGHD, guiding treatment decisions and enabling prenatal or preimplantation genetic testing when familial variants are known.

References

• Clinical Endocrinology • 2012 • Isolated growth hormone deficiency in two siblings because of paternal mosaicism for a mutation in the GH1 gene PMID:21933221
• Human Genetics • 1997 • Two different 5' splice site mutations in the growth hormone gene causing autosomal dominant growth hormone deficiency PMID:9385381
• Growth hormone & IGF Research • 2020 • p.R209H GH1 variant challenges short stature assessment PMID:31835104
• European Journal of Endocrinology • 2016 • A homozygous point mutation in the GH1 promoter (c.-223C>T) leads to reduced GH1 expression in siblings with isolated GH deficiency (IGHD) PMID:27252485
• Growth hormone & IGF Research • 2014 • Autosomal recessive form of isolated growth hormone deficiency is more frequent than the autosomal dominant form in a Brazilian cohort PMID:25116472
• Hormone Research in Paediatrics • 2013 • Splice site mutations in GH1 detected in previously (Genetically) undiagnosed families with congenital isolated growth hormone deficiency type II PMID:24280736
• Endocrinology • 2013 • Endoplasmic reticulum stress and apoptosis contribute to the pathogenesis of dominantly inherited isolated GH deficiency due to GH1 gene splice site mutations PMID:23736291

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