5/26/2023 0 Comments Mical syndromeA common additional feature is postaxial polydactyly, usually affecting both hands and feet (Figure 1A), which is seen in 70–80% of cases ( 5– 7, 9). Meckel–Gruber syndrome is a lethal developmental syndrome characterized by posterior fossa abnormalities (most frequently occipital encephalocele) (Figures 1A,B), bilateral enlarged cystic kidneys (Figures 1C–E), and hepatic developmental defects that include ductal plate malformation associated with hepatic fibrosis and cysts (Figure 1F) ( 8). In the 1960s, the condition was further delineated by Opitz and Howe ( 3) with subsequent refinement of the diagnostic criteria ( 4– 7). Gruber described the same condition later, naming it dysencephalia splanchnocystica ( 2). Meckel noted two siblings who died soon after birth with typical features that included occipital encephalocele, polycystic kidneys, and polydactyly ( 1). Meckel–Gruber syndrome (MKS, OMIM number #249000), sometimes simply termed Meckel syndrome, was first described by Johann Friedrich Meckel in 1822. A common molecular etiology appears to be disruption of ciliary TZ structure and function, affecting essential developmental signaling and the regulation of secondary messengers. We discuss recent insights into the molecular basis of disease in MKS, since the functions of some of the relevant ciliary proteins have now been determined. These include the description of some limited genotype–phenotype correlations. Recent advances in genetic technology, with the widespread use of multi-gene panels for molecular testing, have significantly improved diagnosis, genetic counseling, and the clinical management of MKS families. MKS has a highly variable phenotype, extreme genetic heterogeneity, and displays allelism with other related ciliopathies such as Joubert syndrome, presenting significant challenges to diagnosis. In this review, we provide an up-to-date summary of MKS clinical features, molecular genetics, and clinical diagnosis. Most MKS proteins localize to a distinct ciliary compartment called the transition zone (TZ) that regulates the trafficking of cargo proteins or lipids. It acts as an “antenna” that receives and transduces chemosensory and mechanosensory signals, but also regulates diverse signaling pathways, such as Wnt and Shh, that have important roles during embryonic development. The primary cilium is a microtubule-based organelle, projecting from the apical surface of vertebrate cells. Conditions that are caused by mutations in ciliary genes are collectively termed the ciliopathies, and MKS represents the most severe condition in this group of disorders. Meckel–Gruber syndrome (MKS) is a lethal autosomal recessive congenital anomaly syndrome caused by mutations in genes encoding proteins that are structural or functional components of the primary cilium.
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