A Homozygous Mutation in the Tight-Junction Protein JAM3 Causes Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts

Mochida, Ganeshwaran H.; Ganesh, Vijay; Felie, Jillian M.; Gleason, Danielle; Hill, Rosamund; Clapham, Katharine R.; Rakiec, Daniel P.; Tan, Wen‐Hann; Akawi, Nadia; Al‐Saffar, Muna; Partlow, Jennifer N.; Tinschert, Sigrid; Barkovich, A. James; Ali, Bassam R.; Al‐Gazali, Lihadh; Walsh, Christopher A.

doi:10.1016/j.ajhg.2010.10.026

Cited by 94 publications

(85 citation statements)

References 35 publications

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“…JAM-C −/− mice in the C57BL/6 genetic background developed a severe and progressive hydrocephalus, characterized by extremely enlarged lateral ventricles accompanied by hippocampal dislocation, cortical thinning, loss of proper cortical layering with subsequent reactive gliosis as well as hemorrhages in different brain compartments and obstruction of CSF circulation. In contrast to JAM-C −/− mice in mixed 129Sv - C57BL/6 background, JAM-C −/− C57BL/6 mice therefore mimic part of the CNS pathology recently observed in members a large consanguineous family carrying a rare mutation in JAM-C leading to a non-functional protein [19]. Affected individuals develop a syndrome characterized by severe hemorrhagic destruction of the brain, sub-ependymal calcifications, enlarged ventricles and congenital cataracts partially reflected in JAM-C −/− C57BL/6 mice.…”

Section: Discussionmentioning

confidence: 64%

Junctional Adhesion Molecule (JAM)-C Deficient C57BL/6 Mice Develop a Severe Hydrocephalus

et al. 2012

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The junctional adhesion molecule (JAM)-C is a widely expressed adhesion molecule regulating cell adhesion, cell polarity and inflammation. JAM-C expression and function in the central nervous system (CNS) has been poorly characterized to date. Here we show that JAM-C−/− mice backcrossed onto the C57BL/6 genetic background developed a severe hydrocephalus. An in depth immunohistochemical study revealed specific immunostaining for JAM-C in vascular endothelial cells in the CNS parenchyma, the meninges and in the choroid plexus of healthy C57BL/6 mice. Additional JAM-C immunostaining was detected on ependymal cells lining the ventricles and on choroid plexus epithelial cells. Despite the presence of hemorrhages in the brains of JAM-C−/− mice, our study demonstrates that development of the hydrocephalus was not due to a vascular function of JAM-C as endothelial re-expression of JAM-C failed to rescue the hydrocephalus phenotype of JAM-C−/− C57BL/6 mice. Evaluation of cerebrospinal fluid (CSF) circulation within the ventricular system of JAM-C−/− mice excluded occlusion of the cerebral aqueduct as the cause of hydrocephalus development but showed the acquisition of a block or reduction of CSF drainage from the lateral to the 3rd ventricle in JAM-C−/− C57BL/6 mice. Taken together, our study suggests that JAM-C−/− C57BL/6 mice model the important role for JAM-C in brain development and CSF homeostasis as recently observed in humans with a loss-of-function mutation in JAM-C.

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Section: Discussionmentioning

confidence: 64%

Junctional Adhesion Molecule (JAM)-C Deficient C57BL/6 Mice Develop a Severe Hydrocephalus

et al. 2012

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“…64–66 Familial occurrence of the FBDS phenotype has also been reported, and for these cases, the term fetal brain arrest has been proposed. 67–69 …”

Section: Differential Diagnosismentioning

confidence: 99%

Characterizing the Pattern of Anomalies in Congenital Zika Syndrome for Pediatric Clinicians

et al. 2017

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ontracted through the bite of an infected mosquito or through sexual or other modes of transmission, Zika virus (ZIKV) infection can be prenatally passed from mother to fetus. 1 The virus was first identified in the region of the Americas in early 2015, when local transmission was reported in Brazil. 2 Six months later, a notable increase in the number of infants with congenital microcephaly was observed in northeast Brazil. 3,4 Clinical, epidemiologic, and laboratory evidence led investigators to conclude that intrauterine ZIKV infection was a cause of microcephaly and serious brain anomalies. [5][6][7] However, as with other newly recognized teratogens, these features likely represent a portion of a broader spectrum.A comprehensive review of the English literature, identified by searching Medline and EMBASE for Zika from inception through Sep-tember 30, 2016, was done to better characterize the spectrum of anomalies in fetuses and infants with presumed or laboratoryconfirmed ZIKV infection. A constellation of anomalies that is both consistent and unique, called congenital Zika syndrome (CZS), has emerged but specific components and presumed pathogenetic mechanisms previously have not been well-delineated. [8][9][10] Zika virus infection has spread to more than 45 countries in the Americas and 3 US territories, and, most recently, local transmission was confirmed in the continental United States in the state of Florida. 11 Mosquito-borne transmission of ZIKV in other areas of the United States is possible based on the estimated range of its vectors (Aedes aegypti and Aedes albopictus). 12 Recognition of the CZS phenotype by pediatric clinicians will help ensure appropriate and timely evaluation and follow-up of affected infants.IMPORTANCE Zika virus infection can be prenatally passed from a pregnant woman to her fetus. There is sufficient evidence to conclude that intrauterine Zika virus infection is a cause of microcephaly and serious brain anomalies, but the full spectrum of anomalies has not been delineated. To inform pediatric clinicians who may be called on to evaluate and treat affected infants and children, we review the most recent evidence to better characterize congenital Zika syndrome.OBSERVATIONS We reviewed published reports of congenital anomalies occurring in fetuses or infants with presumed or laboratory-confirmed intrauterine Zika virus infection. We conducted a comprehensive search of the English literature using Medline and EMBASE for Zika from inception through September 30, 2016. Congenital anomalies were considered in the context of the presumed pathogenetic mechanism related to the neurotropic properties of the virus. We conclude that congenital Zika syndrome is a recognizable pattern of structural anomalies and functional disabilities secondary to central and, perhaps, peripheral nervous system damage. Although many of the components of this syndrome, such as cognitive, sensory, and motor disabilities, are shared by other congenital infections, there are 5 features that are rarely seen w...

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“…JamC has been implicated in angiogenic responses although its specific functional purpose during these events was unclear [Lamagna et al, 2005]. A recent study demonstrated mutations in JamC that lead to neonatal lethality in humans due to vascular abnormalities and hemorrhage, particularly in the central nervous system [Mochida et al, 2011]. JamB and JamC are known to interact with each other and, through their cytoplasmic tails, are known to bind the polarity protein Par3 [Ebnet et al, 2003[Ebnet et al, , 2004.…”

Section: Jamb and Jamc Interact With The Polarity Protein Par3 To Conmentioning

confidence: 99%

Molecular Mechanisms Controlling Vascular Lumen Formation in Three-Dimensional Extracellular Matrices

Sacharidou¹,

Stratman²,

Davis³

2011

Cells Tissues Organs

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junction adhesion molecule (Jam)C, JamB, polarity proteins Par3 and Par6b, and the Rho GTPase Cdc42-GTP. These interacting proteins are necessary to stimulate 3D matrix-specific signaling events (including activation of protein kinase cascades that regulate the actin and microtubule cytoskeletons) to control the formation of EC lumens and tube networks. Also, EC lumen formation is directly coupled to the Key WordsEndothelial lumen formation ؒ Tubulogenesis ؒ Lumen signaling complexes ؒ Cdc42 ؒ Rac1 ؒ MT1-MMP ؒ JamB ؒ JamC ؒ Par3 ؒ Par6b ؒ Pericytes ؒ Vascular guidance tunnels ؒ Vascular basement membrane matrix assembly Abstract Considerable progress has been made toward a molecular understanding of how cells form lumen and tube structures in three-dimensional (3D) extracellular matrices (ECM). This progress has occurred through work performed with endothelial and epithelial cell models using both in vitro and in vivo approaches. Despite the apparent similarities between endothelial and epithelial cell lumen and tube formation mechanisms, there are clear distinctions that directly relate to their functional differences. This review will focus on endothelial cell (EC) lumen formation mechanisms which control blood vessel formation during development and postnatal life. Of great interest is that an EC lumen signaling complex has been identified which controls human EC lumen and tube formation in 3D matrices and which coordinates integrin-ECM contacts, cell surface proteolysis, cytoskeletal rearrangements, and cell polarity. This complex consists of the collagen-binding integrin ␣ 2 ␤ 1, the collagen-degrading membrane-type 1 matrix metalloproteinase (MT1-MMP),

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A Homozygous Mutation in the Tight-Junction Protein JAM3 Causes Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts

Cited by 94 publications

References 35 publications

Junctional Adhesion Molecule (JAM)-C Deficient C57BL/6 Mice Develop a Severe Hydrocephalus

Junctional Adhesion Molecule (JAM)-C Deficient C57BL/6 Mice Develop a Severe Hydrocephalus

Characterizing the Pattern of Anomalies in Congenital Zika Syndrome for Pediatric Clinicians

Molecular Mechanisms Controlling Vascular Lumen Formation in Three-Dimensional Extracellular Matrices

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