Elsevier

American Journal of Otolaryngology

Volume 37, Issue 6, November–December 2016, Pages 484-489
American Journal of Otolaryngology

Original contribution
A genetic marker of the ACKR1 gene is present in patients with Type II congenital smell loss who have type I hyposmia and hypogeusia,☆☆,

https://doi.org/10.1016/j.amjoto.2015.07.006Get rights and content

Abstract

Purpose

Our previous study of Type II congenital smell loss patients revealed a statistically significant lower prevalence of an FY (ACKR1, formerly DARC) haplotype compared to controls. The present study correlates this genetic feature with subgroups of patients defined by specific smell and taste functions.

Methods

Smell and taste function measurements were performed by use of olfactometry and gustometry to define degree of abnormality of smell and taste function. Smell loss was classified as anosmia or hyposmia (types I, II or III). Taste loss was similarly classified as ageusia or hypogeusia (types I, II or III). Based upon these results patient erythrocyte antigen expression frequencies were categorized by smell and taste loss with results compared between patients within the Type II group and published controls.

Results

Comparison of antigen expression frequencies revealed a statistically significant decrease in incidence of an Fyb haplotype only among patients with type I hyposmia and any form of taste loss (hypogeusia). In all other patient groups erythrocyte antigens were expressed at normal frequencies.

Conclusions

Data suggest that Type II congenital smell loss patients who exhibit both type I hyposmia and hypogeusia are genetically distinct from all other patients with Type II congenital smell loss. This distinction is based on decreased Fyb expression which correlated with abnormalities in two sensory modalities (hyposmia type I and hypogeusia). Only patients with these two specific sensory abnormalities expressed the Fyb antigen (encoded by the ACKR1 gene on the long arm of chromosome 1) at frequencies different from controls.

Introduction

Congenital smell loss is a condition in which patients are born with significantly deficient olfaction. We have defined two major forms of this abnormality [1]: Type I congenital smell loss patients are distinguished from Type II congenital smell loss patients due to the former’s association with severe somatic, gonadal, and developmental abnormalities (e.g., Kallman syndrome [2]) and the latter’s lack of these clinical abnormalities [1]. Although the character and clinical severity of the olfactory losses between Type I and II congenital smell loss are similar, Type I congenital smell loss is generally associated with anosmia (inability to detect or recognize any odorant) [3] whereas Type II congenital smell loss patients exhibit various degrees of sensory loss including anosmia, type I hyposmia (ability to detect but inability to recognize any odorant), or type II hyposmia (decreased ability to detect and recognize olfactory stimuli) [1]. Some Type II congenital smell loss patients also exhibit hypogeusia [1].

The etiology and genetic factors associated with Type I congenital smell loss have been described extensively [4], [5], [6], [7]. However, no genetic factors had been defined for Type II congenital smell loss despite earlier attempts [8]. In an effort to explore a genetic abnormality present in patients with Type II congenital smell loss, we performed extensive erythrocyte surface antigen testing among these patients [9]. By using olfactometry measurements only [3], we demonstrated that Type II congenital smell loss patients expressed the Fyb (“Duffy b”) antigen at a statistically significantly lower frequency than controls [9]. The gene encoding the Duffy blood group system, formerly known as DARC, has recently been termed atypical chemokine receptor 1 (ACKR1) [10].

We continued this previous work and included both smell and taste abnormalities [3] to evaluate the association with the Fya and Fyb variants of the ACKR1 gene. Five other blood group systems with a total of 16 variants were tested as controls. We hypothesized that the patients’ observed abnormalities may be genetic and present ACKR1 as a candidate gene region for further studies in clinically distinct patient cohorts or families who have Type II congenital smell loss with type I hyposmia and hypogeusia.

Section snippets

Patients

Ninety-nine patients [aged 6–70; 30 ± 16 years (mean ± SD); 44 men and 55 women] with lifelong smell loss without associated somatic abnormalities or hypogonadism were previously described [9]. Each patient exhibited normal growth, gonadal function, and development for their age without family history of olfactory or other sensory disorders in their offspring. Physical examination of each patient’s head and neck revealed no clinical abnormalities. Radiological studies of the brain revealed that

Results

Previously we reported that patients with Type II congenital smell loss have a statistically significant lower prevalence of an FY (ACKR1, formerly DARC) haplotype compared to controls. Here, we explored the hypothesis that this FY haplotype may correlate with distinct subgroups of the same patient cohort.

Patients with hyposmia (which all patients exhibited) could be differentiated further by presence or absence of abnormalities in taste function. Patients with type I hyposmia could be

Discussion

Although comparison of erythrocyte surface antigen expression frequencies does not offer insight into the specific genetics and pathophysiology of patients with Type II congenital smell loss, it suggests that there are genetic factors in some patients with Type II congenital smell loss that separate them from the general population. Were there no genetic or hereditary association, the patients would be expected to closely resemble the general population with regard to the frequency of

Conclusion

Patients with Type II congenital smell loss presenting with both type I hyposmia and hypogeusia express the Fyb (“Duffy b”) erythrocyte antigen at a significantly lower frequency compared to healthy controls and to all other patients with Type II congenital smell loss. Type II congenital smell loss patients with other kinds of sensory loss (including type I hyposmia without hypogeusia) express Fyb and all other tested antigens at frequencies that are similar to those of the published control.

Acknowledgment

We acknowledge Sherry Lynne Sheldon, Agnes Hallie Lee-Stroka and Rebecca Page Perry for coordinating the serologic testing in the Department of Transfusion Medicine of the NIH Clinical Center, where this research was supported in part by the Intramural Research Program (Grant/Project ID Z99 CL999999).

References (18)

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    It has been shown to act as a growth or transcription factor in the taste system [28]. In the absence of this moiety taste buds are inhibited in their growth and development anatomically [3–31]. With their reintroduction taste buds grow and develop based upon Shh stimulation of taste bud stem cells [30].

  • Initiation of smell function in patients with congenital hyposmia

    2016, American Journal of Otolaryngology - Head and Neck Medicine and Surgery
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    Type II represents 88% of patients [1,2]. They do not have a family history of smell loss and do not have significant brain, somatic or defined genetic abnormalities [1,2,5]. Despite these differences, both types have similar degrees of loss of smell function [1,2,5].

Funding: Intramural Research Program of the NIH Clinical Center (partially).

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Conflict of Interest: Robert I. Henkin is a member of the board of directors of Cyrano Therapeutics. None of the other authors has a conflict of interest, financial or otherwise with respect to the publication of this manuscript.

Statement of Disclaimer: The views expressed do not necessarily represent the view of the National Institutes of Health, the Department of Health and Human Services, or the U.S. Federal Government.

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