Background: Silver Russell syndrome (SRS) is a heterogeneous disorder characterised by intrauterine and post-natal growth retardation, relative macrocephaly, protruding forehead, feeding difficulties and body asymmetry. Variants in HMGA2 are a rare cause of SRS and despite strong evidence for the crucial role of HMGA2 in growth regulation, its functional role in human linear growth is unclear.
Methods: Patients with variants in the HMGA2 gene were phenotyped. Single nucleotide substitutions were created by mutagenesis of an N-terminal FLAG tagged-HMGA2 cDNA whilst a frameshift construct was customized to recapitulate reading frame extension. HMGA2 protein expression and nuclear localisation were assessed by immunoblotting and confocal microscopy. Two Hmga2 knock-in mouse models were generated by CRISPR/Cas9 technology.
Results: We report five novel variants in five unrelated individuals (height SDS ranging from -3.2 to -3.9) occurring in different critical regions of the HMGA2 gene. These include two stop-gain nonsense variants (c.49G>T, c.52C>T), two frameshift variants (c.144delC, c.145delA) leading to an identical prolonged protein and a missense variant, c.166A>G (p.K56E), located in the linker 2 region of HMGA2. Phenotypic features were highly variable. However, microcephaly appeared to be a highly penetrant and consistent feature in these patients. Nuclear localisation was markedly reduced or absent for all variants except c.166A>G. Transgenic mice homozygous for Hmga2K56E present with significant growth impairment and demonstrate for the first time, that a single amino acid change located outside of AT-hook domains, can modulate growth in mice. A further Hmga2Ter76 knock-in mouse model for a Hmga2 protein lacking a functional third AT-hook and the C-terminus, results in a pygmy phenotype and infertility.
Conclusions: We report a heterogeneous group of individuals with SRS harbouring variants in HMGA2 and describe the first Hmga2 missense knock-in mouse model (Hmga2K56E) causing a growth restricted phenotype. In undiagnosed patients with clinical features of SRS but negative molecular/genetic analysis, HMGA2 testing should be considered, particularly in those presenting with microcephaly.
21 Sep 2023 - 23 Sep 2023