Abstract
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. 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. The primary cilium is a microtubule-based organelle, projecting from the apical surface of vertebrate cells. 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. Most MKS proteins localize to a distinct ciliary compartment called the transition zone (TZ) that regulates the trafficking of cargo proteins or lipids. In this review, we provide an up-to-date summary of MKS clinical features, molecular genetics, and clinical diagnosis. 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. 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. These include the description of some limited genotype–phenotype correlations. 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. A common molecular etiology appears to be disruption of ciliary TZ structure and function, affecting essential developmental signaling and the regulation of secondary messengers.
Highlights
Specialty section: This article was submitted to Pediatric Nephrology, a section of the journal Frontiers in Pediatrics
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
Most MKS proteins localize to a distinct ciliary compartment called the transition zone (TZ) that regulates the trafficking of cargo proteins or lipids
Summary
Meckel–Gruber syndrome (MKS, OMIM number #249000), sometimes termed Meckel syndrome, was first described by Johann Friedrich Meckel in 1822. Meckel noted two siblings who died soon after birth with typical features that included occipital encephalocele, polycystic kidneys, and polydactyly [1]. 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]. A common additional feature is postaxial polydactyly, usually affecting both hands and feet (Figure 1A), which is seen in 70–80% of cases [5,6,7, 9]. Renal cystic dysplasia is the most characteristic feature of MKS, but differs from those typical of polycystic kidney disease. In addition to cystic kidney dysplasia, hepatic involvement is an obligate feature of MKS [6]. The typical histology shows bile duct proliferation and dilation (Figure 1F), associated with excess collagenous connective tissues [8], which are thought to arise from the incomplete development of the hepatic biliary system [16, 17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
