Zonulopathies as Genetic Disorders of the Extracellular Matrix

The zonular fibres are formed primarily of fibrillin-1, a large extracellular matrix (ECM) glycoprotein, and also contain other constituents such as LTBP-2, ADAMTSL6, MFAP-2 and EMILIN-1, amongst others. They are critical for sight, holding the crystalline lens in place and being necessary for accommodation. Zonulopathies refer to conditions in which there is a lack or disruption of zonular support to the lens and may clinically be manifested as ectopia lens (EL)-defined as subluxation of the lens outside of the pupillary plane or frank displacement (dislocation) into the vitreous or anterior segment. Genes implicated in EL include those intimately involved in the formation and function of these glycoproteins as well as other genes involved in the extracellular matrix (ECM). As such, genetic pathogenic variants causing EL are primarily disorders of the ECM, causing zonular weakness by (1) directly affecting the protein components of the zonule, (2) affecting proteins involved in the regulation of zonular formation and (3) causing the dysregulation of ECM components leading to progressive zonular weakness. Herein, we discuss the clinical manifestations of zonulopathy and the underlying pathogenetic mechanisms.