<i>CCBE1</i> mutations can cause a mild, atypical form of generalized lymphatic dysplasia but are not a common cause of non‐immune hydrops fetalis

Connell, FC; Kalidas, Kamini; Østergaard, Pia; Brice, Glen; Murday,; Mortimer, P. S.; Jeffrey, I; Jeffery, Steve; Mansour, Sahar

doi:10.1111/j.1399-0004.2011.01731.x

Cited by 20 publications

(15 citation statements)

References 8 publications

(13 reference statements)

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“…Mutations in class I phosphoinositide 3-kinases ( PI3K ) that lead to AKT hyperphosphorylation are associated with Lymphatic Malformations (LM) in humans (112). LEC migratory factor CCBE1 mutations in humans cause a type of lymphatic dysplasia known as Hennekam syndrome (22, 201, 202). Point mutations in human FOXC2 are associated with lymphedema-distichiasis (LD) syndrome (132, 317), in which lymphatic valves are defective.…”

Section: Development Of Lymphatic Vessel Networkmentioning

confidence: 99%

Lymphatic Vessel Network Structure and Physiology

Breslin

Yang

Scallan

et al. 2018

Comprehensive Physiology

264

258

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The lymphatic system is comprised of a network of vessels interrelated with lymphoid tissue, which has the holistic function to maintain the local physiologic environment for every cell in all tissues of the body. The lymphatic system maintains extracellular fluid homeostasis favorable for optimal tissue function, removing substances that arise due to metabolism or cell death, and optimizing immunity against bacteria, viruses, parasites, and other antigens. This article provides a comprehensive review of important findings over the past century along with recent advances in the understanding of the anatomy and physiology of lymphatic vessels, including tissue/organ specificity, development, mechanisms of lymph formation and transport, lymphangiogenesis, and the roles of lymphatics in disease.

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Section: Development Of Lymphatic Vessel Networkmentioning

confidence: 99%

Lymphatic Vessel Network Structure and Physiology

Breslin

Yang

Scallan

et al. 2018

Comprehensive Physiology

264

258

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“…The collagen‐ and calcium‐binding EGF‐like domains 1 protein (CCBE1) is an extracellular matrix protein described to be essential for budding and/or migration of lymphatic ECs from the anterior cardinal veins, and also for angiogenic sprouting from venous endothelium during embryogenesis (Hogan et al, ; Bos et al, ). In humans, mutations in CCBE1 were identified in patients with Hennekam syndrome, which displays an array of severe symptoms including lymphangiectasia, primary lymphedema, and heart defects, among others (Van Balkome et al, ; Alders et al, ; Alders et al, ; Conell et al, 2010; Conell et al, ; Shah et al, ). In accordance with these findings, the lymphatic vasculature is completely absent in both Ccbe1 mouse mutant lines, the one lacking the first two gene exons (which code for the signal peptide; Ccbe1 tm1Lex ) (Bos et al, ; Hägerling et al, ) and the one lacking the CCBE1 collagen‐binding domains (Roukens et al, ).…”

Section: Introductionmentioning

confidence: 99%

CCBE1 is required for coronary vessel development and proper coronary artery stem formation in the mouse heart

Bonet

Pereira

Bover

et al. 2018

Developmental Dynamics

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“…Furthermore, Connell et al reported homozygous CCBE1 C75S mutation in a kindred with three affected siblings, all of whom presented in utero with fetal hydrops, but two died and the third sibling survived and displayed HS [4]. While lymphatic dysplasia may be commonly associated with CCBE1 mutations, CCBE1 mutations are not a common cause of fetal hydrops [17, 33]. The fact that the same mutation can give rise to different phenotypes implies that environmental forces and/or loci other than CCBE1 are involved.…”

Section: Discussionmentioning

confidence: 99%

A Multiplex Kindred with Hennekam Syndrome due to Homozygosity for a CCBE1 Mutation that does not Prevent Protein Expression

et al. 2015

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Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1) bi-allelic mutations have been associated with syndromes of widespread congenital lymphatic dysplasia, including Hennekam Syndrome (HS). HS is characterized by lymphedema, lymphangiectasia, and intellectual disability. CCBE1 encodes a putative extracellular matrix protein but the HS-causing mutations have not been studied biochemically. We report two HS siblings, born to consanguineous parents of Turkish ancestry, whose clinical phenotype also includes protein losing enteropathy, painful relapsing chylous ascites, and hypogammaglobulinemia. We identified by whole exome and Sanger sequencing the homozygous CCBE1 C174Y mutation in both siblings. This mutation had been previously reported in another HS kindred from the Netherlands. In over-expression studies, we found increased intracellular expression of all forms (monomers, dimers, trimers) of the CCBE1 C174Y mutant protein, by Western blot, despite mutant mRNA levels similar to wild-type (WT). In addition, we detected increased secretion of the mutant CCBE1 protein by ELISA. We further found the mutant and WT proteins to be evenly distributed in the cytoplasm, by immunofluorescence and confocal microscopy. Finally, we found a strong decrease of lymphatic vessels, with a corresponding diminished expression of CCBE1, by immunohistochemistry of the patients’ intestinal biopsies. In contrast, mucosal blood vessels and muscularis mucosae showed normal CCBE1 staining. Our findings show that the mutant CCBE1 C174Y protein is not loss-of-function by loss-of-expression.

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CCBE1 mutations can cause a mild, atypical form of generalized lymphatic dysplasia but are not a common cause of non‐immune hydrops fetalis

Cited by 20 publications

References 8 publications

Lymphatic Vessel Network Structure and Physiology

Lymphatic Vessel Network Structure and Physiology

CCBE1 is required for coronary vessel development and proper coronary artery stem formation in the mouse heart

A Multiplex Kindred with Hennekam Syndrome due to Homozygosity for a CCBE1 Mutation that does not Prevent Protein Expression

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