Genetic causes of growth hormone insensitivity beyond GHR

Abstract

Growth hormone insensitivity (GHI) syndrome, first described in 1966, is classically associated with monogenic defects in the GH receptor (GHR) gene which result in severe post-natal growth failure as consequences of insulin-like growth factor I (IGF-I) deficiency. Over the years, recognition of other monogenic defects downstream of GHR has greatly expanded understanding of primary causes of GHI and growth retardation, with either IGF-I deficiency or IGF-I insensitivity as clinical outcomes. Mutations in IGF1 and signaling component STAT5B disrupt IGF-I production, while defects in IGFALS and PAPPA2, disrupt transport and release of circulating IGF-I, respectively, affecting bioavailability of the growth-promoting IGF-I. Defects in IGF1R, cognate cell-surface receptor for IGF-I, disrupt not only IGF-I actions, but actions of the related IGF-II peptides. The importance of IGF-II for normal developmental growth is emphasized with recent identification of defects in the maternally imprinted IGF2 gene. Current application of next-generation genomic sequencing has expedited the pace of identifying new molecular defects in known genes or in new genes, thereby expanding the spectrum of GH and IGF insensitivity. This review discusses insights gained and future directions from patient-based molecular and functional studies.

Keywords: GH insensitivity; GH-IGF-I axis; IGF-I deficiency; IGF-I insensitivity.

Fig 1.

Schematic of the human GH-IGF-I axis. Interaction of GH with cell surface dimeric GH receptors (GHR) leads to recruitment of Janus kinase 2 (JAK2), and subsequent activation of multiple signaling cascades. Recruited STAT5B is tyrosine phosphorylated by JAK2, homodimerizes, and translocate to the nucleus, where it binds DNA, regulating production of circulating IGF-I, IGFBP-3 and ALS. PAPPA2 proteolysis of circulating IGFBP-3 and -5, generates free IGF-I. Mutations in a number of components along this axis result in GHI and IGF deficiency (STAT5B, IGF1), IGF bioavailability (IGFALS, PAPPA2) or IGF resistance (IGF1R). Co-morbidities associated with mutations are indicated.

Fig 2.

STAT5B mutations. (A) Schematic of human STAT5B protein and corresponding exons based on transcript NM_012448.4. Homozygous mutations (black) and dominant-negative mutations (red) are indicated. ND, N-terminal domain; CCD, coiled-coiled domain; DBD, DNA binding domain; L, linker; SH2, ν-src homology 2; TAD, transcriptional activation domain. Y⁶⁹⁹, tyrosine 699 that is phosphorylated. (B) mutations tabulated. #, siblings; $, includes family members.

Fig 3.

Rare homozygous IGF1 mutations. (A) Three major IGF1 transcripts expressed by most tissues, are from promotor P1. Exons correlating to propeptides, consisting of signal peptide (residue 1 – 32) followed by common domains B, C, A and D encoded by exons 3 and 4, and variable domain E which is post-translationally removed; (B) Homozygous IGF1 mutations are indicated and tabulated.

Fig 4.

Human PAPPA2 mutations. (A) Schematic of protein and exons encoding the protein. The two described mutations are indicated. (B) A simplified model proposing that the negative feedback loop of circulating IGF-I for regulating GH secretion is dependent on free IGF-I availability.

Fig 5.

Schematic of IGF1R protein and encoding exons. Sample of mutations from the ^~60 reported, are shown, scattered along the gene. Homozygous, in blue; severest compound heterozygous mutations, boxed. Remaining mutations are heterozygous and autosomal dominant. L1 and L2, receptor L-domains; CR, Cysteine-rich region; FN, fibronectin type-III regions; TM, transmembrane domain, TK, tyrosine kinase domain; CT, C-terminal region.

Fig 6.

Schematic of Human IGF2 protein and encoding exons. (A) Of the two transcripts shown, NM_000612, encoding the canonical IGF-II protein, is the basis for cDNA and protein nomenclature in 11 of 12 mutations reported. The nomenclature of the first mutation was based on NM_001127598 (130). IGF-II peptide structure is similarly organized as IGF-I; (B) The 11 germline, non-mosaic, mutations are schematically indicated, based on exons of NM_000612.6, and tabulated. The one reported mosaic mutation (139) is not shown.