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Mutations in CCBE1 Cause Generalized Lymph Vessel Dysplasia

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Mutations in CCBE1 Cause Generalized Lymph Vessel Dysplasia BRIEF COMMUNICATIONS Mutations in CCBE1 cause (Fig. 1a–f)8. Subsequently, subjects with lymphangiectasias in pleura, pericardium, thyroid gland and kidney and with hydrops fetalis were generalized lymph vessel dysplasia described9,10. The entity was designated lymphedema-lymphangiectasia– mental retardation or Hennekam syndrome (MIM 235510). Occurrence in humans of affected siblings, equal occurrence among sexes and frequent consanguinity indicated autosomal recessive inheritance9. 1 2 2 1 Marielle Alders , Benjamin M Hogan , Evisa Gjini , Faranak Salehi , We collected blood samples from a series of 27 subjects with Hennekam 3 4 5 Lihadh Al-Gazali , Eric A Hennekam , Eva E Holmberg , syndrome born to 22 families. None of the subjects carried mutations 1 6 7,8 Marcel M A M Mannens , Margot F Mulder , G Johan A Offerhaus , in FLT4, FOXC2 or SOX18. We performed homozygosity mapping in 5 9 10 Trine E Prescott , Eelco J Schroor , Joke B G M Verheij , three unpublished subjects (A, B and C) originating from a small isolate 2 11,14 12 Merlijn Witte , Petra J Zwijnenburg , Mikka Vikkula , in The Netherlands. Pedigree analysis had shown the parents of subject 2,15 13–15 Stefan Schulte-Merker & Raoul C Hennekam A to be consanguineous and all three subjects to be related (Fig. 1g). We reasoned that occurrence of three cases of a rare disorder in a small Lymphedema, lymphangiectasias, mental retardation and isolate suggested homozygosity for a founder mutation. Homozygosity unusual facial characteristics define the autosomal recessive mapping identified a 5.7-Mb homozygous region on chromosome 18q21 Hennekam syndrome. Homozygosity mapping identified a with identical haplotypes in the three affected individuals (Fig. 1h and critical chromosomal region containing CCBE1, the human Supplementary Table 1). The region contained 29 genes. Additional ortholog of a gene essential for lymphangiogenesis in zebrafish. homozygosity mapping in two subjects (D, E) born to different consan- Homozygous and compound heterozygous mutations in guineous parents11 (Fig. 1g) identified several stretches of homozygosity, seven subjects paired with functional analysis in a zebrafish including a segment on 18q21. The overlapping homozygous region was model identify CCBE1 as one of few genes causing primary 0.5 Mb long and contained four genes (Fig. 1h). generalized lymph-vessel dysplasia in humans. Of particular interest was CCBE1, encoding Collagen and Calcium- Binding EGF-domain-1, a secreted protein (Supplementary Figs. 1 The lymphatic system comprises a vascular system separate from the and 2) required for embryonic lymphangiogenesis in zebrafish12. cardiovascular system, essential for immune responses, fluid homeo- Sequencing CCBE1 revealed homozygous mutations in all five subjects stasis and fat absorption. Lymphatic vessels develop in a complex pro- (Supplementary Fig. 3 and Supplementary Table 2). Mutations in sub- cess termed lymphangiogenesis that involves budding, migration and jects A, B and C (C75S) and subject D (C102S) are N-terminal of the proliferation of lymphatic endothelial progenitor cells1–3. A few genes, putative calcium-binding EGF domain. This region also shows EGF-like © All rights reserved. 2009 Inc. Nature America, such as FLT4 (ref. 4), FOXC2 (ref. 5) and SOX18 (ref. 6), are known to sequences containing cysteine residues that are highly conserved, suggest- be critically involved in lymph vessel formation in humans. ing functional relevance. The mutation G327R in subject E is predicted to Disturbances of lymphangiogenesis usually cause disruption of the disrupt the glycine backbone in the putative collagen helix of CCBE1. drainage of interstitial fluids into the cardiovascular system, resulting Subsequently, we screened 19 more families with Hennekam syn- in lymphedema, chylothorax or pleural effusion, chylous ascites, and drome for CCBE1 mutations and found compound heterozygous angiectasias of lymph vessels in intestines and other organs7. Signs of CCBE1 mutations in two affected individuals (F, G) (Supplementary lymph-vessel dysplasias are commonly limited to the limbs1. In 1989, an Fig. 3 and Supplementary Table 2): subject F carried a maternally inbred family was described in which four mentally retarded members inherited, single-nucleotide insertion, c.683_684insT, which intro- had a widespread congenital lymphatic malformation syndrome with duces an in-frame premature stop codon, leading to either production limb lymphedema, and lymphangiectasias of the intestine and at a later of protein lacking the collagen domain or nonsense-mediated mRNA age also of the lungs8. In addition, affected individuals had unusual facial decay13. In addition, subject F carried a paternally inherited mis- characteristics (flat face, flat and broad nasal bridge, hypertelorism) sense mutation, R158C. Subject G was compound heterozygous for thought to reflect the extent of early intrauterine facial lymphedema c.683_684insT and C174R (Supplementary Table 2). Both R158C and 1Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands. 2Hubrecht Institute – Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Centre, Utrecht, The Netherlands. 3Department of Paediatrics and Pathology, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates. 4Department of Clinical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 5Department of Medical Genetics, Oslo University Hospital, Rikshospitalet, Oslo, Norway. 6Department of Pediatrics, Free University Medical Center, Amsterdam, The Netherlands. 7Department of Pathology, University Medical Centre Utrecht, Utrecht, The Netherlands. 8Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands. 9Department of Pediatrics Amalia, Isala Clinics, Zwolle, The Netherlands. 10Department of Clinical Genetics, University Medical Centre Groningen, Groningen, The Netherlands. 11Department of Clinical Genetics, Free University Medical Center, Amsterdam, The Netherlands. 12Laboratory of Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium. 13Clinical and Molecular Genetics Unit, Institute of Child Health, Great Ormond Street Hospital for Children, University College London, London, UK. 14Department of Pediatrics, Academic Medical Centre, Amsterdam, The Netherlands. 15These authors contributed equally to this work. Correspondence should be addressed to R.C.H. ([email protected]). Received 8 June; accepted 13 October; published online 22 November 2009; doi:10.1038/ng.484 1272 VOLUME 41 | NUMBER 12 | DECEMBER 2009 NATURE GEnETICS B R I E F C O M M U N I C AT I O N S a b c d e f g h Subject Mb AB C DE rs1434511 45 18q21.1 rs2928927 50 rs1145315 18q21.2 Subject B LMAN1 Subject A Subject C 18q21.31 rs64592 CPLX1 55 CCBE1 rs19443418 rs7244048 GLUDP4 18q21.32 © All rights reserved. 2009 Inc. Nature America, rs1506330 18q21.33 rs1381548 Subject E Subject D 60 rs1472948 Figure 1 Phenotypes of subjects with generalized lymphatic dysplasia and homozygosity mapping in five subjects with consanguineous parents. (a) Subject D, with flat face, hypertelorism and flat nasal bridge. (b) Subject G, with widespread congenital lymphedema and distended abdomen due to ascites. (c,d) Subject F, showing webbing of the neck as result of intrauterine lymphedema, limb lymphedema, distended abdomen due to ascites, and muscle wasting at 20 years. (e) Distended lymph vessels in the intestinal wall of subject F (see also Supplementary Fig. 6). (f) Uneven endothelial podoplanin staining in lymphangiectasia (small intestine, subject F). (g) Pedigrees of the subjects with consanguineous parents. Affected subjects are shown as filled circles (females) or squares (males). All parents tested were heterozygous carriers (dot). (h) Homozygous regions at chromosome 18q21, indicating a shared homozygous region of 0.5 Mb. Bars, homozygous segments; flanking SNPs are indicated. C174R are in the calcium-binding EGF domain, the first introducing knockdown (morphant) phenotypes, whereas mutant mRNA does an extra cysteine that might interfere with proper folding of the pro- not. Therefore this model is suitable for testing pathogenicity of tein and the second disrupting a conserved cysteine residue predicted missense mutations identified in this study. to form disulfide bonds important for the secondary structure of this We introduced homologous mutations in zebrafish ccbe1 and domain (Fig. 2a). All mutations were absent in controls of Western tested the ability to rescue the ccbe1 morphant phenotype (Fig. 2b–i). European (n = 100) or Arabic (to match the ethnic background of Injection of wild-type ccbe1 mRNA reliably rescued the absence of the subject D; n = 97) descent. None of the other subjects from 17 families thoracic duct (Fig. 2b–d,j). Three of the five mutant mRNAs tested carrying Hennekam syndrome harbored a CCBE1 mutation. (C94S, C166R and G313R, equivalent to human C102S, C174R and The function of ccbe1 (ref. 12) has been studied in a zebrafish lymph- G327R, respectively) were not able to confer any rescue (Fig. 2f,h–j; angiogenesis model14,15. Zebrafish ccbe1 mutants lack parachordal Supplementary Fig. 4). Mutant C67S (equivalent to human C75S) lymphangioblasts and all known lymphatic vessels. Mutants develop showed weak rescue, and R150C (equivalent to human R158C) more lymphedema but retain a largely normal cardiovascular system. Wild- robust rescue comparable to that seen with wild
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