BSPED2022 Oral Communications Oral Communications 8 (5 abstracts)
Characterisation of the first heterozygous missense HMGA2 variant helps delineate the crucial functional roles of a novel growth gene
Emily Cottrell 1 , Avinaash Maharaj 1 , Barbara Triggs-Raine 2 , Thatchawan Thanasupawat 2 , Jack Williams 1 , Masanobu Fujimoto 3 , Hermine A. Van Duyvenvoorde 4 , Christiaan De Bruin 4 , Sjoerd Joustra 4 , Sarina Kant 5 , Danielle Van der Kaay 5 , Maria Inmaculada Castilla de Cortázar Larrea 6 , Ahmed Massoud 7 , Louise A Metherell 1 , Vivian Hwa 3 , Sabine Hombach-Klonisch 2 , Thomas Klonisch 2 & Helen L. Storr 1
1Centre for Endocrinology, William Harvey Research Institute, QMUL, London, United Kingdom; 2University of Manitoba, Manitoba, Canada; 3Cincinnati Children’s Hospital, Cincinnati, USA; 4Leiden University Medical Centre, Leiden, Netherlands; 5Erasmus Medical Centre, Rotterdam, Netherlands; 6Monterrey Institute of Technology and Higher Education, Monterrey, Mexico; 7Northwick Park Hospital, London, United Kingdom
Background: Silver Russell syndrome (SRS) is genetically heterogenous and around 30% of patients with clinical SRS have no genetic diagnosis. Point mutations in HMGA2 have been reported in 4 patients worldwide causing growth failure and an SRS-like phenotype. Despite strong evidence of the crucial role of HMGA2 in growth across species, the mechanism of action of HMGA2 in human linear growth is unclear.
Objective: Identify and functionally characterise HMGA2 mutations in a patients with growth failure and SRS features.
Methods: We used custom bioinformatic pipelines to filter genetic data generated from our novel targeted genome short stature gene panel. Our Dutch collaborators identified further novel HMGA2 variants of interest. Our novel missense HMGA2 variant was functionally assessed using Electrophoretic Mobility Shift Assays (EMSAs). Our Canadian collaborators generated novel Hmga2K56E transgenic mice using CRISPR/Cas technology.
Results: We identified 6 novel heterozygous HMGA2 variants in patients with growth failure and SRS features. This includes the first heterozygous missense mutation c.166A>G, p.(Lys56Glu) in a patient with pre- and post-natal growth failure, low BMI, triangular face and high arched palate; 3/6 NH-CSS. The variant was predicted pathogenic (CADD score 27.2; Mutation taster: disease causing) and was inherited from her mother who had short stature and similar facial features. This novel variant resides in a critically important region of HMGA2, adjacent to the second AT hook/DNA binding region. This missense variant substitutes lysine, a positively charged amino acid crucial for DNA binding at target sites, for glutamic acid, a negatively charged amino acid. EMSAs confirmed reduced binding of the mutant c.166A>G HMGA2 protein to target DNA sequences. Transgenic mice harbouring homozygous c.166A>G p.(Lys56Glu) mutations (Hmga2K56E) displayed dysmorphic facial features similar to the phenotypes observed in SRS children. Hmga2K56E transgenic mice were fertile but small for gestational age and showed SRS-like dwarfism.
Conclusions: We report the largest HMGA2 case series to date including the first heterozygous missense mutation. Binding to DNA target sites was impaired in the mutant c.166A>G HMGA2 protein. A novel transgenic Hmga2K56E mouse model recapitulated the SRS phenotype seen in our patient, confirming the critical functional importance of this amino acid residue.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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