Decoding Clinical Diversity in Monogenic TGFBR1 and TGFBR2 Mutations: Insights into the Interplay of Molecular Mechanisms and Hypomorphicity

Fadia M. Abu-Sailik¹Nesrin Gariballa¹Bassam R Ali^1,2*

• ¹United Arab Emirates University, Al-Ain, Abu Dhabi, United Arab Emirates
• ²ASPIRE Precision Medicine Research Institute, United Arab Emirates University, Al-Ain, Abu Dhabi, United Arab Emirates

Several autosomal-dominant monogenic disorders have been conclusively associated withmutations in TGFBR1 and TGFBR2, key receptors of the Transforming Growth Factor-β(TGFβ) signaling pathway. Although these disorders share a common cardiovascularconnective tissue manifestation, different mutations present with strikingly distinctive clinicalpresentations leading to distinct disorders, including Loeys-Dietz syndrome (LDS), Marfansyndrome type 2 (MFS2), and Thoracic Aortic Aneurysms and Dissections (TAAD). Inaddition, some mutations lead to Shprintzen-Goldberg syndrome (SGS), which ischaracterized by skeletal deformities and intellectual disabilities in addition to thecardiovascular involvement, or vascular Ehlers-Danlos Syndrome (vEDS) that is associatedwith spontaneous rupture of the main arteries and internal organs. Furthermore, MultipleSelf-healing Squamous Epithelioma (MSSE), a rare familial skin cancer, is linked tomutations in these genes. This significant phenotypic variability observed in these disorderscould be attributed to various factors, ranging from the nature of the mutation including itslocation within the protein, the variable functional impact of the mutations (hypomorphicity),the level of disruption to the intricate interactions between signaling pathways, and theinfluence of modifier genes or environmental factors. In addition to haploinsufficiency, theimpairment of TGFβ signaling could be exacerbated in other scenarios, such as the dominant-negative effects, in which a mutant allele disrupts the normal activity of the wild-type proteinby forming non-functional receptor oligomers, hindering their trafficking. This review shedslight on these hereditary disorders, highlighting the broad spectrum of their clinicalpresentations associated with mutations in the same gene, their pathophysiology, andunderlying molecular mechanisms. Most crucially, it underscores the critical gaps in ourcurrent understanding while proposing compelling directions for future research. This reviewalso emphasizes the pressing need to unravel the complex genotype-phenotype correlations,which could pave the way for more precise diagnostic and therapeutic strategies.