Original contributionA genetic marker of the ACKR1 gene is present in patients with Type II congenital smell loss who have type I hyposmia and hypogeusia☆,☆☆,★
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.
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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).
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2016, American Journal of Otolaryngology - Head and Neck Medicine and SurgeryCitation Excerpt :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 SurgeryCitation Excerpt :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].
Genetics of congenital olfactory dysfunction: a systematic review of the literature
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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.
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