Assessment of the Olfactory Function in Italian Patients with Type 3 von Willebrand Disease Caused by a Homozygous 253 Kb Deletion Involving VWF and TMEM16B/ANO2

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.

Cyclic-nucleotide–gated cation current and Ca2+-activated Cl current elicited by odorant in vertebrate olfactory receptor neurons

“…One simple reason would be a species difference between mouse and frog, but this is perhaps unlikely because the Cl current is such a robust phenomenon. Furthermore, some human patients with type-3 von Willebrand disease happened to have a simultaneously disrupted Ano2 gene and these individuals did show some behavioral olfactory defects, although it is still uncertain now whether this genotype-phenotype correlation is authentic, that is, causal (20,36,63). In any case, our experiments on mouse ORNs (64) are in progress and will provide the answer upon completion.…”

Six-Month Psychophysical Evaluation of Olfactory Dysfunction in Patients with COVID-19

“…The number of correct answers was calculated according to the test manual. As the names of 6 odorants reported in the UPSIT test have previously been shown not to match the common perception of those odorants by the Italian population leading to misidentification > 20% in a population of normal subjects, a reduced and culturally adapted version of the Italian UPSIT (CA-UPSIT) including 34 odorants that had been identified correctly by more than 80% of normal subjects, was used to evaluate the sense of smell in our subjects according to Cenedese et al (Cenedese et al, 2015) and Parola et al (Parola and Liberini, 1999). The following scores on a scale of 0-34 have been used: probable malingering, 00-04; total anosmia, 05-15; severe microsmia, 16-19; moderate microsmia, 20-23; mild microsmia, 24-27; normosmia, 28-34. A c c e p t e d M a n u s c r i p t…”

High prevalence of long-term psychophysical olfactory dysfunction in patients with COVID-19

“…As the names of 6 odorants reported in the UPSIT test have previously been shown not to match the common perception of those odorants by the Italian population leading to misidentification > 20% in a population of normal subjects, a reduced and culturally adapted version of the Italian UPSIT (CA-UPSIT) including 34 odorants that had been identified correctly by more than 80% of normal subjects, was used to evaluate the sense of smell in our subjects according to Cenedese et al . (Cenedese et al, 2015) and Parola et al . (Parola and Liberini, 1999).…”

“…Published control data on healthy Italian subjects of age comprised between 21 and 57 years reported a mean CA-UPSIT score of 32 with 98% normosmic and 2% mild microsmic subjects (Cenedese et al, 2015). Take into account that smell identification ability declined markedly only after the seventh decade (Doty et al, 1984a) and that only 15.2% of patients in the present series aged older than 69 years, our data confirm the presence of a significant olfactory impairment at 6-month.…”