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lymphedema_gene_ccbe1

Lymphedema Gene CCBE1

Much new research has been done in the area of the genetic causes of lymphedema and researchers have noe identified the CCBE1 as responsible for Hennekem Lymphangiectasia Lymphedema Syndrome.

This is exciting to see as it moves us closer and closer to understanding what specific mutations cause specific lymphedema syndromes and is another step in perhaps a gene therapy for us.

Pat

COLLAGEN AND CALCIUM-BINDING EGF DOMAIN-CONTAINING PROTEIN 1; CCBE1

OMIM612753

Alternative titles; symbols

KIAA1983

Gene map locus 18q21.32

CLONING

By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2001) cloned CCBE1, which they designated KIAA1983. The transcript contains a repetitive element in its 3-prime end, and the deduced protein contains 418 amino acids. RT-PCR ELISA detected highest expression in ovary and much lower expression in fetal liver and in adult lung, liver, and kidney. Much weaker expression was detected in all other adult and fetal tissues examined.

MAPPING

Hartz (2009) mapped the CCBE1 gene to chromosome 18q21.32 based on an alignment of the CCBE1 sequence (GenBank AB075863) with the genomic sequence (build 36.1).

MOLECULAR GENETICS

In 5 affected individuals from consanguineous families with Hennekam lymphangiectasia-lymphedema syndrome (235510) mapping to chromosome 18q21, including 3 patients from a Dutch pedigree, 1 Omani patient, and 1 Iraqi patient, Alders et al. (2009) sequenced the candidate gene CCBE1 and identified homozygosity for missense mutations in all 5 patients (612753.0001-612753.0003, respectively). Analysis of CCBE1 in 19 additional families with Hennekam syndrome identified 2 unrelated probands who were compound heterozygotes for a nonsense mutation (612753.0004) and 2 different missense mutations (612753.0005 or 612753.0006).

ANIMAL MODEL

Hogan et al. (2009) described a zebrafish mutant called 'full of fluid' (fof) that lacked the thoracic duct and intersegmental and dorsal longitudinal lymphatic vessels, but retained an apparently normal blood vasculature. Hogan et al. (2009) found fof zebrafish had a mutation in the Ccbe1 gene. In wildtype zebrafish, Ccbe1 was expressed spatially and temporally in the migration routes of lymphatic endothelial cells, but not in lymphatic endothelial cells themselves. Ccbe1 acted at the same stage of development as Vegfc (601528) and was required for lymphangioblast budding and angiogenic sprouting from venous endothelium. Hogan et al. (2009) concluded that CCBE1 may be a guidance molecule that regulates lymphangioblast budding and possibly migration.

ALLELIC VARIANTS

(selected examples)

.0001 HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME [CCBE1, CYS75SER]

In 3 affected members of a consanguineous Dutch pedigree with Hennekam lymphangiectasia-lymphedema syndrome (235510), Alders et al. (2009) identified homozygosity for a 223T-A transversion in the CCBE1 gene, resulting in a cys75-to-ser (C75S) substitution at a residue N-terminal of the putative calcium-binding EGF domain. The unaffected parents of all 3 patients were heterozygous for the mutation, which was not found in 100 western European controls. In a zebrafish lymphangiogenesis model, mutant mRNA equivalent to human C75S showed weak rescue of the morphant phenotype, indicating preservation of some protein function.

.0002 HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME [CCBE1, CYS102SER]

In a 7-year-old boy with Hennekam lymphangiectasia-lymphedema syndrome (235510) from a consanguineous Omani family, Alders et al. (2009) identified homozygosity for a 305G-C transversion in the CCBE1 gene, resulting in a cys102-to-ser (C102S) substitution at a residue N-terminal of the putative calcium-binding EGF domain. The unaffected parents were heterozygous for the mutation, which was not found in 97 Iraqi controls. In a zebrafish lymphangiogenesis model, mutant mRNA equivalent to human C102S was not able to confer any rescue of the morphant phenotype.

.0003 HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME [CCBE1, GLY237ARG]

In a 5-year-old girl with Hennekam lymphangiectasia-lymphedema syndrome (235510) from a consanguineous Iraqi family, Alders et al. (2009) identified homozygosity for a 979G-C transversion in the CCBE1 gene resulting in a gly237-to-arg (G237R) substitution predicted to disrupt the glycine backbone in the putative collagen helix. The unaffected parents were heterozygous for the mutation, which was not found in 97 Iraqi controls. In a zebrafish lymphangiogenesis model, mutant mRNA equivalent to human G237R was not able to confer any rescue of the morphant phenotype.

.0004 HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME [CCBE1, 1-BP INS, 683T]

In a 20-year-old Dutch man and a 1-year-old Norwegian boy with Hennekam lymphangiectasia-lymphedema syndrome (235510), Alders et al. (2009) identified compound heterozygosity for a 1-bp insertion (683_684insT) in the CCBE1 gene, resulting in an in-frame premature termination codon predicted to cause production of protein lacking the collagen domain or nonsense-mediated decay, and a missense mutation (612753.0005 or 612753.0006, respectively). None of the mutations was found in 100 western European controls.

.0005 HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME [CCBE1, ARG158CYS]

In a 20-year-old Dutch man with Hennekam lymphangiectasia-lymphedema syndrome (235510), Alders et al. (2009) identified compound heterozygosity for a 472C-T transition in the CCBE1 gene, resulting in an arg158-to-cys (R158C) substitution that introduces an extra cysteine predicted to interfere with proper folding of the protein, and a nonsense mutation (612753.0004). In a zebrafish lymphangiogenesis model, mutant mRNA equivalent to human R158C showed rescue of the morphant phenotype comparable to that seen with wildtype, indicating some preservation of protein function.

.0006 HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME [CCBE1, CYS174ARG]

In a 1-year-old Norwegian boy with Hennekam lymphangiectasia-lymphedema syndrome (235510), Alders et al. (2009) identified compound heterozygosity for a 520T-C transition in the CCBE1 gene, resulting in a cys174-to-arg (C174R) substitution at a conserved residue predicted to form disulfide bonds important for the secondary structure of the calcium-binding EGF domain, and a nonsense mutation (612753.0004). In a zebrafish lymphangiogenesis model, mutant mRNA equivalent to human C174R was not able to confer any rescue of the morphant phenotype.

REFERENCES

1. Alders, M.; Hogan, B. M.; Gjini, E.; Salehi, F.; Al-Gazali, L.; Hennekam, E. A.; Holmberg, E. E.; Mannens, M. M. A. M.; Mulder, M. F.; Offerhaus, G. J. A.; Prescott, T. E.; Schroor, E. J.; Verheij, J. B. G. M.; Witte, M.; Zwijnenburg, P. J.; Vikkula, M.; Schulte-Merker, S.; Hennekam, R. C. : Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nature Genet. 41: 1272-1274, 2009. PubMed ID : 19935664 2. Hartz, P. A. : Personal Communication. Baltimore, Md., 4/15/2009. 3. Hogan, B. M.; Bos, F. L.; Bussmann, J.; Witte, M.; Chi, N. C.; Duckers, H. J.; Schulte-Merker, S. : ccbe1 is required for embryonic lymphangiogenesis and venous sprouting. Nature Genet. 41: 396-398, 2009. PubMed ID : 19287381 4. Nagase, T.; Kikuno, R.; Ohara, O. : Prediction of the coding sequences of unidentified human genes. XXII. The complete sequences of 50 new cDNA clones which code for large proteins. DNA Res. 8: 319-327, 2001. PubMed ID : 11853319 CONTRIBUTORS

Marla J. F. O'Neill - updated : 12/14/2009

CREATION DATE

Patricia A. Hartz : 4/22/2009

EDIT HISTORY

alopez : 12/21/2009 terry : 12/14/2009 alopez : 4/22/2009

OMIM

HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME

OMIM #235510

TEXT

A number sign (#) is used with this entry because of evidence that Hennekam lymphangiectasia-lymphedema syndrome can be caused by mutation in the CCBE1 gene (612753).

CLINICAL FEATURES

Hennekam et al. (1989) described a syndrome of intestinal lymphangiectasia with severe lymphedema of the limbs, genitalia, and face, and severe mental retardation. Intestinal lymphangiectasia was accompanied by the usual hypoproteinemia, hypogammaglobulinemia, and lymphocytopenia. Facial anomalies included flat face, flat nasal bridge, hypertelorism, epicanthal folds, small mouth, tooth anomalies, and ear defects. The facial appearance was Oriental. Down syndrome had been suspected in some of the patients. The patients had seizures. Erysipelas was a problem complicating the edema of the legs. Autosomal recessive inheritance was strongly supported by the occurrence of the disorder in 2 males and 2 females of 2 sibships from parents who shared a common ancestral couple. Hennekam et al. (1989) reviewed genetic syndromes with lymphangiectasia and lymphedema as features.

Gabrielli et al. (1991) reported a male, born of second-cousin parents, with facial anomalies, syndactyly of the fingers, equinovarus feet, and cryptorchidism present at birth. He had had soft and abundant feces most of his life. He was first hospitalized at age 4 for leg edema and was found to have hypoalbuminemia, hypogammaglobulinemia, and lymphopenia. Conductive hearing loss was demonstrated at age 9 years. Gabrielli et al. (1991) provided photographs of the patient at age 14 years. The typical face was characterized by flat midface, flat nasal bridge, hypertelorism, epicanthal folds, small mouth, tooth anomalies, and small ears. The hand showed cutaneous syndactyly and camptodactyly. Seizures were thought to be related to hypocalcemia; however, it would seem that the ionized calcium may be normal. Pachygyria was demonstrated that may account for mental retardation and seizures.

Yasunaga et al. (1993) described the case of a 7-year-old boy with protein-losing gastroenteropathy. He had a face typical of Hennekam syndrome, including flat nasal bridge, hypertelorism, small mouth and tooth anomalies, but did not have mental retardation or severe lymphedema. Yasunaga et al. (1993) suggested that the child had a mild form of Hennekam syndrome. Study of the family in 3 generations suggested that heterozygotes may have some of the facial features.

Cormier-Daire et al. (1995) described a girl with intestinal lymphangiectasia, severe lymphedema of the limbs, seizures, mild mental retardation, and facial anomalies consistent with the diagnosis of Hennekam syndrome. In addition, she had an ectopic kidney and craniosynostosis of the coronal suture, 2 manifestations not previously reported in this disorder.

Scarcella et al. (2000) described 2 sisters with facial anomalies, protein-losing enteropathy, and intestinal lymphangiectasia consistent with the diagnosis of Hennekam syndrome. Both had a number of other anomalies not previously described in this disorder: primary hypothyroidism, hypertrophic pyloric stenosis, and an early fatal outcome at 8 and 3 months, respectively. Polyhydramnios complicated each pregnancy in the third trimester. At birth the older sister had flat face with flat and broad nasal bridge, short philtrum, hypertelorism, gingival hypertrophy, and mild retrognathia; the younger sister had similar features. Hepatosplenomegaly and lymphedema of the limbs developed in the first month of life in the first born. She died from a severe septic event at 8 months of age, after having recurrent gastroenteric and gastroenteric and respiratory infections associated with severe hypogammaglobulinemia. Autopsy showed extensive lymphangiomatosis of the mediastinum, pleura and peritoneum, and intestinal lymphangiectasia. Fetal hepatomegaly was detected in the second born, who died at 3 months of age from cardiac failure due to severe refractory hypoproteinemia.

Forzano et al. (2002) reported an Italian patient with severe lymphedema of the lower limbs, genitalia, and face, intestinal lymphangiectasia, seizures, and moderate mental retardation. He had a flat face, depressed nasal bridge, and hypertelorism. Forzano et al. (2002) proposed that the patient had a severe form of Hennekam syndrome.

Van Balkom et al. (2002) reported 8 patients with Hennekam syndrome and compared their findings with those of the 16 previously reported cases. Lymphedema was usually congenital, sometimes markedly asymmetric, and often gradually progressive. Complications, such as erysipelas, were common. Lymphangiectasias were found in the intestines and occasionally in the pleura, pericardium, thyroid gland, and kidney. Several patients demonstrated congenital cardiac and blood vessel anomalies, suggesting a disturbance in angiogenesis. Typical facial features included flat face, flat and broad nasal bridge, and hypertelorism, but the features were variable and thought to mirror the extent of intrauterine facial lymphedema. Other anomalies included glaucoma, dental anomalies, hearing loss, and renal anomalies. Psychomotor development varied widely, even within a single family, from almost normal development to severe mental retardation. Convulsions were common. The existence of 10 familial cases, equal sex ratio, increased parental consanguinity rate, and absence of vertical transmission were consistent with an autosomal recessive pattern of inheritance.

Bellini et al. (2003) described a female infant with congenital lymphedema, facial anomalies, and intestinal lymphangiectasia consistent with a diagnosis of Hennekam syndrome. At birth, the patient presented with severe respiratory distress due to nonimmune hydrops fetalis, a congenital chylothorax, and pulmonary lymphangiectasia.

Al-Gazali et al. (2003) reported 4 children from 4 inbred Arab families with varying manifestations of Hennekam syndrome as well as additional features, including abnormalities of the middle ear, anomalous pulmonary venous drainage, interrupted inferior vena cava, polysplenia, crossed renal ectopia, median position of the liver, and multiple cavernous haemangiomas. Since anomalies of the veins and the consequent developmental abnormalities of the lymphatics might lead to alterations in the fluid balance of the embryo, Al-Gazali et al. (2003) hypothesized that altered fluid dynamics due to defective vascular and lymphatic development might disrupt critical events in craniofacial morphogenesis, resulting in Hennekam syndrome.

MAPPING

In a large consanguineous Dutch pedigree with Hennekam syndrome, Alders et al. (2009) performed homozygosity mapping and identified a 5.7-Mb homozygous region on chromosome 18q21; additional homozygosity mapping in 2 unrelated probands with Hennekam syndrome from consanguineous families revealed several stretches of homozygosity, including an overlapping 0.5-Mb interval on 18q21 containing 4 genes.

MOLECULAR GENETICS

In 5 affected individuals from consanguineous families with Hennekam syndrome, including 3 patients from a Dutch pedigree, 1 Omani patient, and 1 Iraqi patient, Alders et al. (2009) sequenced the candidate gene CCBE1 (612753) and identified homozygosity for missense mutations in all 5 patients (612753.0001-612753.0003, respectively). Analysis of CCBE1 in 19 additional families with Hennekam syndrome identified 2 unrelated probands who were compound heterozygotes for a nonsense mutation (612753.0004) and another missense mutation (612753.0005 and 612753.0006, respectively). Unaffected parents were heterozygous for the mutations, which were not found in 100 western European or 97 Arabic controls. Alders et al. (2009) noted that mutations were detected in only 5 (23%) of 22 families with Hennekam syndrome, indicating genetic heterogeneity.

REFERENCES

1. Al-Gazali, L. I.; Hertecant, J.; Ahmed, R.; Khan, N. A.; Padmanabhan, R. : Further delineation of Hennekam syndrome. Clin. Dysmorph. 12: 227-232, 2003. PubMed ID : 14564208 2. Alders, M.; Hogan, B. M.; Gjini, E.; Salehi, F.; Al-Gazali, L.; Hennekam, E. A.; Holmberg, E. E.; Mannens, M. M. A. M.; Mulder, M. F.; Offerhaus, G. J. A.; Prescott, T. E.; Schroor, E. J.; Verheij, J. B. G. M.; Witte, M.; Zwijnenburg, P. J.; Vikkula, M.; Schulte-Merker, S.; Hennekam, R. C. : Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nature Genet. 41: 1272-1274, 2009. PubMed ID : 19935664 3. Bellini, C.; Mazzella, M.; Arioni, C.; Campisi, C.; Taddei, G.; Toma, P.; Boccardo, F.; Hennekam, R. C.; Serra, G. : Hennekam syndrome presenting as nonimmune hydrops fetalis, congenital chylothorax, and congenital pulmonary lymphangiectasia. Am. J. Med. Genet. 120A: 92-96, 2003. PubMed ID : 12794699 4. Cormier-Daire, V.; Lyonnet, S.; Lehnert, A.; Martin, D.; Salomon, R.; Patey, N.; Broyer, M.; Ricour, C.; Munnich, A. : Craniosynostosis and kidney malformation in a case of Hennekam syndrome. Am. J. Med. Genet. 57: 66-68, 1995. PubMed ID : 7645602 5. Forzano, F.; Faravelli, F.; Loy, A.; Di Rocco, M. : Severe lymphedema, intestinal lymphangiectasia, seizures and mild mental retardation: further case of Hennekam syndrome with a severe phenotype. Am. J. Med. Genet. 111: 68-70, 2002. PubMed ID : 12124738 6. Gabrielli, O.; Catassi, C.; Carlucci, A.; Coppa, G. V.; Giorgi, P. : Intestinal lymphangiectasia, lymphedema, mental retardation, and typical face: confirmation of the Hennekam syndrome. Am. J. Med. Genet. 40: 244-247, 1991. PubMed ID : 1897580 7. Hennekam, R. C. M.; Geerdink, R. A.; Hamel, B. C. J.; Hennekam, F. A. M.; Kraus, P.; Rammeloo, J. A.; Tillemans, A. A. W. : Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation. Am. J. Med. Genet. 34: 593-600, 1989. PubMed ID : 2624276 8. Scarcella, A.; De Lucia, A.; Pasquariello, M. B.; Gambardella, P. : Early death in two sisters with Hennekam syndrome. Am. J. Med. Genet. 93: 181-183, 2000. PubMed ID : 10925377 9. Van Balkom, I. D. C.; Alders, M.; Allanson, J.; Bellini, C.; Frank, U.; De Jong, G.; Kolbe, I.; Lacombe, D.; Rockson, S.; Rowe, P.; Wijburg, F.; Hennekam, R. C. M. : Lymphedema-lymphangiectasia-mental retardation (Hennekam) syndrome: a review. Am. J. Med. Genet. 112: 412-421, 2002. PubMed ID : 12376947 10. Yasunaga, M.; Yamanaka, C.; Mayumi, M.; Momoi, T.; Mikawa, H. : Protein-losing gastroenteropathy with facial anomaly and growth retardation: a mild case of Hennekam syndrome. Am. J. Med. Genet. 45: 477-480, 1993. PubMed ID : 8465855 CONTRIBUTORS

Marla J. F. O'Neill - updated : 12/14/2009 Siobhan M. Dolan - updated : 1/29/2004 Victor A. McKusick - updated : 6/23/2003 Deborah L. Stone - updated : 6/17/2003 Victor A. McKusick - updated : 8/8/2002

CREATION DATE

Victor A. McKusick : 2/6/1990

EDIT HISTORY

alopez : 12/21/2009 terry : 12/14/2009 mgross : 3/17/2004 carol : 1/29/2004 cwells : 6/30/2003 terry : 6/23/2003 carol : 6/17/2003 carol : 8/13/2002 tkritzer : 8/13/2002 tkritzer : 8/9/2002 terry : 8/8/2002 carol : 8/29/2000 terry : 8/17/2000 mark : 6/20/1995 mimadm : 2/19/1994 carol : 3/2/1993 supermim : 3/16/1992 carol : 10/3/1991 supermim : 3/20/1990

OMIM

Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans.

Nat Genet. 2009 Dec;41(12):1272-4.

Alders M, Hogan BM, Gjini E, Salehi F, Al-Gazali L, Hennekam EA, Holmberg EE, Mannens MM, Mulder MF, Offerhaus GJ, Prescott TE, Schroor EJ, Verheij JB, Witte M, Zwijnenburg PJ, Vikkula M, Schulte-Merker S, Hennekam RC.

Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands. Lymphedema, lymphangiectasias, mental retardation and unusual facial characteristics define the autosomal recessive Hennekam syndrome. Homozygosity mapping identified a critical chromosomal region containing CCBE1, the human ortholog of a gene essential for lymphangiogenesis in zebrafish. Homozygous and compound heterozygous mutations in seven subjects paired with functional analysis in a zebrafish model identify CCBE1 as one of few genes causing primary generalized lymph-vessel dysplasia in humans.

http://www.nature.com/ng/journal/v41/n12/abs/ng.484.htmlNature

Lymphedema Family Study - Genetics

This is perhaps one of the most important centers for us as lymphedema patients. The pace of genetic research is exploding and it will be through this type of research that we will come to know and understand:

1.) What causes lymphedema - the genetics involved.

2.) The path to a genetic cure

3,) The ability to provide treatment.

How many times have we said, “we wished someone could find out what causes lymphedema?” Countless, countless times.

The serious problem we face now is that due to the economy funding programs for this research has almost dried up and the program in very much in danger of being shutdown early next year.

Friends, we absolutely must save this program. Should it be closed, we would loose just about our only hope of a cure. We would also loose some of the most committed doctors, and support staff.

Please visit the site and go through their information. Support them as much as it is possible.

Pat O'Connor

University of Pittsburg

Lymphedema People Resources

lymphedema_gene_ccbe1.txt · Last modified: 2012/10/16 14:40 (external edit)