MONDO: 0030316;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p34.2 | Lymphatic malformation 11 | 619401 | Autosomal dominant | 3 | TIE | 600222 |
A number sign (#) is used with this entry because of evidence that lymphatic malformation-11 (LMPHM11) is caused by heterozygous mutation in the TIE1 gene (600222) on chromosome 1p34.
Lymphatic malformation-11 (LMPHM11) is characterized by lower extremity edema, with onset in the second or third decade of life. Some affected individuals may have subclinical lymphatic malformations (Michelini et al., 2020).
For a discussion of genetic heterogeneity of lymphatic malformation, see LMPHM1 (153100).
Michelini et al. (2020) studied 3 Italian female probands with lymphedema and mutation in the TIE1 gene. The first was a 23-year-old woman who was diagnosed with lower extremity edema at age 13 years. Her mother, who was clinically unaffected, was shown to have mild defects of the lymphatic system on lymphoscintigraphy, and her maternal grandmother reported episodes of cyclic edema. The second proband was a 52-year-old woman with edema of the right lower leg since age 25 years. No family history was reported. The third proband was a 47-year-old woman with bilateral lymphedema of the legs below the knees, which was diagnosed at age 15 years. Her mother also had lymphedema.
The transmission pattern of lymphatic malformation in the families reported by Michelini et al. (2020) was consistent with autosomal dominant inheritance.
In a cohort of 235 Italian patients with lymphedema who were negative for mutation in known lymphedema-associated genes, Michelini et al. (2020) tested for new candidate genes and identified 3 probands with heterozygous mutations in the TIE1 gene (see, e.g., 600222.0001 and 600222.0002). The mutations, which segregated with disease in the 2 families for whom DNA was available, were found in gnomAD at low minor allele frequencies.
Shen et al. (2014) generated conditional knockout mice deficient in Tie1 and observed the development of subcutaneous edema by embryonic day (E) 13.5. Only two-thirds of the mutant mice were alive at E18.5, and of those born alive, none survived. Lymph sac formation took place, but remodeling of the primary lymphatic network to form collecting vessels did not occur, and no lymphatic valves were detected. Condensation of lymphatic endothelial cells, an initial step in valve development, was also not seen in the Tie1-null mice. Mice with a postnatally induced Tie1 deletion showed a significant decrease in lymphatic ring structure in the tail skin, and developed edema of the paws. In addition, lymphatic vessels were sparse and disorganized in the ear skin of the mutant mice.
Michelini, S., Ricci, M., Veselenyiova, D., Kenanoglu, S., Kurti, D., Baglivo, M., Fiorentino, A., Basha, S. H., Priya, S., Serrani, R., Krajcovic, J., Dundar, M., Dautaj, A., Bertelli, M. TIE1 as a candidate gene for lymphatic malformations with or without lymphedema. Int. J. Molec. Sci. 21: 6780, 2020. [PubMed: 32947856] [Full Text: https://doi.org/10.3390/ijms21186780]
Shen, B., Shang, Z., Wang, B., Zhang, L., Zhou, F., Li, T., Chu, M., Jiang, H., Wang, Y., Qiao, T., Zhang, J., Sun, W., Kong, X., He, Y. Genetic dissection of tie pathway in mouse lymphatic maturation and valve development. Arterioscler. Thromb. Vasc. Biol. 34: 1221-1230, 2014. [PubMed: 24764452] [Full Text: https://doi.org/10.1161/ATVBAHA.113.302923]