Abstract
Type 3 Von Willebrand disease is an autosomal recessive disease caused by the virtual absence of the von Willebrand factor (VWF). A rare 253 kb gene deletion on chromosome 12, identified only in Italian and German families, involves both the VWF gene and the N-terminus of the neighbouring TMEM16B/ANO2 gene, a member of the family named transmembrane 16 (TMEM16) or anoctamin (ANO). TMEM16B is a calcium-activated chloride channel expressed in the olfactory epithelium. As a patient homozygous for the 253 kb deletion has been reported to have an olfactory impairment possibly related to the partial deletion of TMEM16B, we assessed the olfactory function in other patients using the University of Pennsylvania Smell Identification Test (UPSIT). The average UPSIT score of 4 homozygous patients was significantly lower than that of 5 healthy subjects with similar sex, age and education. However, 4 other members of the same family, 3 heterozygous for the deletion and 1 wild type, had a slightly reduced olfactory function indicating that socio-cultural or other factors were likely to be responsible for the observed difference. These results show that the ability to identify odorants of the homozygous patients for the deletion was not significantly different from that of the other members of the family, showing that the 253 kb deletion does not affect the olfactory performance. As other genes may compensate for the lack of TMEM16B, we identified some predicted functional partners from in silico studies of the protein-protein network of TMEM16B. Calculation of diversity for the corresponding genes for individuals of the 1000 Genomes Project showed that TMEM16B has the highest level of diversity among all genes of the network, indicating that TMEM16B may not be under purifying selection and suggesting that other genes in the network could compensate for its function for olfactory ability.
Highlights
The von Willebrand disease (VWD) is a hereditary coagulation abnormality in humans caused by qualitative or quantitative defects of the von Willebrand factor (VWF), a protein involved in hemostasis [1]
We measured the odorant identification ability of Italian patients affected by type 3 VWD caused by a 253 kb deletion in chromosome 12 producing the deletion of the VWF gene and of the N-terminus of the neighboring TMEM16B gene
Our results reveal that homozygous patients for the deletion have a slightly reduced ability in identifying odorants compared to healthy subjects
Summary
The von Willebrand disease (VWD) is a hereditary coagulation abnormality in humans caused by qualitative (type 2 VWD) or quantitative defects (type 1 and type 3 VWD) of the von Willebrand factor (VWF), a protein involved in hemostasis [1]. Type 3 VWD is caused by VWF mutations producing absence of VWF [3]. Inheritance of type 3 VWD is autosomal recessive and this disorder has a prevalence of about 0.5–3 individuals per million [4, 5]. Mutations of VWF causing type 3 VWD include nonsense mutations, splicing defects, insertions, and deletions (http://www.vwf.group.shef.ac.uk). Schneppenheim et al [10] investigated patients with large deletions from unrelated German and Italian families. They found that a 253 kb deletion in chromosome 12 results in the deletion of the VWF gene and the deletion of the N-terminus of the neighbouring TMEM16B gene
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