Identifying candidate genes underlying isolated congenital anosmia

Kamarck, Marissa L.; Trimmer, Casey; Murphy, Nicolle R.; Gregory, Kristen M.; Manoel, Diogo; Logan, Darren W.; Saraiva, Luis R.; Mainland, Joel D.

doi:10.1111/cge.14470

Cited by 4 publications

(3 citation statements)

References 67 publications

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“…ICA is a genetically heterogeneous disorder, with only nine implicated genes (CNGA2, TENM1, PROKR2, PROK2, FGFR1, SEM3A, CHD7, ANOS1, FGF8). A recently published study that used whole-exome sequencing in 10 families and 141 individuals with ICA confirmed the involvement of the CNGA2 gene as an essential component of the olfactory transduction pathway and further identified a loss-of-function variant in SREK1IP1, with a role in zinc ion binding, suggesting a potential influence on olfactory signaling [21].…”

Section: Introductionmentioning

confidence: 81%

“…Anosmia can thus be related to dementia, such as in Parkinson's or Alzheimer's disease, or it can be present at birth (congenital) or of unknown cause (idiopathic) [20]. The underlying causes of congenital anosmia, which can be syndromic (part of a syndrome, such as Kallmann syndrome) or nonsyndromic (isolated congenital anosmia, ICA), remain largely unknown [21]. ICA is a genetically heterogeneous disorder, with only nine implicated genes (CNGA2, TENM1, PROKR2, PROK2, FGFR1, SEM3A, CHD7, ANOS1, FGF8).…”

Section: Introductionmentioning

confidence: 99%

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The Molecular Basis of Olfactory Dysfunction in COVID-19 and Long COVID

Anastassopoulou,

Davaris,

Ferous

et al. 2024

Lifestyle Genomics

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Olfactory dysfunction (OD) is not uncommon following viral infection. Herein, we explore the interplay of host genetics with viral correlates in coronavirus disease 2019 (COVID-19)- and long COVID-related OD, and its diagnosis and treatment that remain challenging. Two genes associated with olfaction, UGT2A1 and UGT2A2, appear to be involved in COVID-19-related anosmia, a hallmark symptom of acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), particularly in the early stages of the pandemic. SARS-CoV-2 infects olfactory support cells, sustentacular and Bowman gland cells, that surround olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) where the initial step of odor detection takes place. Anosmia primarily arises from the infection of support cells of the OE, followed by the deciliation and disruption of OE integrity, typically without OSN infection. Through the projected axons of OSNs, the virus could theoretically reach the olfactory bulb and brain, but current evidence points against this route. Intriguingly, SARS-CoV-2 infection of support cells leads to profound alterations in the nuclear architecture of OSNs, leading to the downregulation of odorant receptor-related genes, e.g., of Adcy3. Viral factors associated with the development of OD include spike protein aminoacidic changes, e.g., D614G, the first substitution that was selected early during SARS-CoV-2 evolution. More recent variants of the Omicron family are less likely to cause OD compared to Delta or Alpha, although OD has been associated with a milder disease course. OD is one of the most prevalent post-acute neurologic symptoms of SARS-CoV-2 infection. The tens of millions of people worldwide who have lingering problems with OD wait eagerly for effective new treatments that will restore their sense of smell which adds value to their quality of life.

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Section: Introductionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

The Molecular Basis of Olfactory Dysfunction in COVID-19 and Long COVID

Anastassopoulou,

Davaris,

Ferous

et al. 2024

Lifestyle Genomics

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“…Human SREK1IP1 has also been identified as an interactor of METHYLTRANSFERASE LIKE 16 (METTL16; Covelo-Molares et al, 2021), one of the two enzymes that catalyze the deposition of N 6 -methyladenosine (m 6 A) epitranscriptomic marks onto mRNAs and U6 small nuclear RNA (snRNA) (Warda et al, 2017). Dominant frameshift alleles of SREK1IP1 have been associated with congenital anosmia (Kamarck et al, 2024).…”

Section: Introductionmentioning

confidence: 99%

CXIP4 depletion causes early lethality and pre-mRNA missplicing in Arabidopsis

Aceituno-Valenzuela,

Fontcuberta-Cervera,

Micol-Ponce

et al. 2024

Preprint

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Zinc knuckle (ZCCHC) motif-containing proteins are present in unicellular and multicellular eukaryotes and most ZCCHC proteins with known functions participate in the metabolism of various classes of RNA, such as mRNAs, ribosomal RNAs, and microRNAs. The Arabidopsis (Arabidopsis thaliana) genome encodes 69 ZCCHC-containing proteins, but the functions of most remain unclear. One of these proteins is CAX-INTERACTING PROTEIN 4 (CXIP4), which has been classified as a PTHR31437 family member, along with human SREK1-interacting protein 1 (SREK1IP1), which is thought to function in pre-mRNA splicing and RNA methylation. Metazoan SREK1IP1-like and plant CXIP4-like proteins only share a ZCCHC motif, and their functions remain almost entirely unknown. We studied two loss-of-function alleles of ArabidopsisCXIP4, the first mutations in PTHR31437 family genes described to date:cxip4-1is likely null and shows early lethality, andcxip4-2is hypomorphic and viable, with pleiotropic morphological defects. Thecxip4-2mutant exhibited deregulation of defense genes and upregulation of transcription factor encoding genes, some of which might explain its developmental defects. This mutant also exhibited increased intron retention events, and the specific functions of misspliced genes, such as those involved in “gene silencing by DNA methylation” and “mRNA polyadenylation factor” suggest that CXIP4 has additional functions. The CXIP4 protein localizes to the nucleus in a pattern resembling nuclear speckles, which are rich in splicing factors. Therefore,CXIP4is required for plant survival and proper development, and mRNA maturation.

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Humans without a sense of smell breathe differently

Gorodisky,

Honigstein,

Weissbrod

et al. 2024

Nat Commun

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Olfaction may play a restricted role in human behavior, yet paradoxically, its absence in anosmia is associated with diverse deleterious outcomes, culminating in reduced life expectancy. The mammalian nose serves two purposes: olfaction and breathing. Because respiratory patterns are impacted by odors, we hypothesized that nasal respiratory airflow may be altered in anosmia. We apply a wearable device that precisely logs nasal airflow for 24-hour-long sessions in participants with isolated congenital anosmia and controls. We observe significantly altered patterns of respiratory nasal airflow in anosmia in wake and in sleep. These differences allow classification of anosmia at 83% accuracy using the respiratory trace alone. Patterns of respiratory airflow have pronounced impact on health, emotion and cognition. We therefore suggest that a portion of the deleterious outcomes associated with anosmia may be attributed to altered patterns of respiratory nasal airflow rather than a direct result of lost odor perception per se.

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Identifying candidate genes underlying isolated congenital anosmia

Cited by 4 publications

References 67 publications

The Molecular Basis of Olfactory Dysfunction in COVID-19 and Long COVID

The Molecular Basis of Olfactory Dysfunction in COVID-19 and Long COVID

CXIP4 depletion causes early lethality and pre-mRNA missplicing in Arabidopsis

Humans without a sense of smell breathe differently

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