Olfactory Dysfunction in Patients WithCNGB1-Associated Retinitis Pigmentosa

Abstract

etinitis pigmentosa (RP) (OMIM 26800) is a genetically heterogeneous disease characterized by poor night vision and loss of peripheral visual field owing to a decline in rod-dependent vision. Later in the disease course, cones and thus the central visual field and visual acuity may also be affected. Retinitis pigmentosa is caused by mutations in genes coding for proteins involved in photoreceptor function, structure, and/or maintenance. When the gene product is expressed exclusively in the retina or when its lack is compensated for in other tissues, the disease remains restricted to the retina. However, significant expression of the gene product in other organs may result in syndromic RP with morphological and/or functional consequences affecting other organs. Cyclic nucleotide-gated (CNG) channels are key components for signal transduction in photoreceptors and olfactory sensory neurons (OSNs). 1 They function as tetramers composed of α and β subunits. Specific types of heterotetramers are expressed in different sensory cells. For example, the rod CNG channel consists of 3 CNGA1 subunits and 1 CNGB1 subunit, 2 the cone CNG channel consists of 3 CNGA3 subunits and 1 CNGB3 subunit, 3,4 and the CNG channel of OSNs (olfCNG) consists of 2 CNGA2 subunits, 1 CNGA4 subunit, and 1 CNGB1b subunit. 5 Therefore, only the CNGB1 subunit is involved in both photoreceptor and olfactory signal transduction. In contrast to most CNGA subunits that are regarded as main subunits IMPORTANCE Co-occurrence of retinitis pigmentosa (RP) and olfactory dysfunction may have a common genetic cause. OBJECTIVE To report olfactory function and the retinal phenotype in patients with biallelic mutations in CNGB1, a gene coding for a signal transduction channel subunit expressed in rod photoreceptors and olfactory sensory neurons. DESIGN, SETTING, AND PARTICIPANTS This case series was conducted from August 2015 through July 2017. The setting was a multicenter study involving 4 tertiary referral centers for inherited retinal dystrophies. Participants were 9 patients with CNGB1-associated RP. MAIN OUTCOMES AND MEASURES Results of olfactory testing, ocular phenotyping, and molecular genetic testing using targeted next-generation sequencing. RESULTS Nine patients were included in the study, 3 of whom were female. Their ages ranged between 34 and 79 years. All patients had an early onset of night blindness but were usually not diagnosed as having RP before the fourth decade because of slow retinal degeneration. Retinal features were characteristic of a rod-cone dystrophy. Olfactory testing revealed reduced or absent olfactory function, with all except one patient scoring in the lowest quartile in relation to age-related norms. Brain magnetic resonance imaging and electroencephalography measurements in response to olfactory stimulation were available for 1 patient and revealed no visible olfactory bulbs and reduced responses to odor, respectively. Molecular genetic testing identified 5 novel (c.1312C>T, c.2210G>A, c.2492+1G>A, c.2763C>G, and c.3044_3050...

Variable expressivity in patients with autosomal recessive retinitis pigmentosa associated with the gene CNGB1

“…The variant c.2492 + 1 G > A has been associated with anosmia patients with arRP due to compound heterozygous mutations in CNGB1 (19). Here we tested extended family members who were carriers of a single CNGB1 mutation (c.2957A>T or c.2492 + 1 G > A) with the SIT.…”

“…Thus, patient E1, who had a homozygous mutation, c.1431 C > A (p.Cys477*) is expected to be normosmic since the mutation would not be expressed in olfactory neurons. On the other hand, Issa et al (19) reported that a patient with a homozygous mutation, c.1312 C > T (p.(Gln438*) had hyposmia that was borderline high. This is curious since the spliced transcript expressed in the nasal sensory neurons would translate a normal CNGB1a protein subunit.…”

“…We identified nine variants in CNGB1 that were likely to explain the arRP from eight independent families (Table 2). Six variants were novel, and three variants have been previously described (19,(31)(32)(33)(34). Two novel variants, c.2127 C > G, p. Phe709Leu and c.2092 T > C, p.Cys698Arg were nonsynonymous substitutions (missense) hat altered highly conserved amino acid residues (Table 3).…”

“…Both CNGA1 and CNGB1 have been associated with arRP and similarly characterized by early-onset nyctalopia, concentric loss of the visual field, macular involvement, and progressive visual acuity decline (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Mutations CNGB1 and CNGA2 but not CNGA1 have been linked to recessive olfactory dysfunction (19)(20)(21).…”

Awareness of olfactory impairment in a cohort of patients with CNGB1-associated retinitis pigmentosa

“…1,2 A subsequent quantitative study found objectively reduced olfactory function in 8 of 9 patients tested (89%), with 3 patients (33%) aware of their olfactory impairment. 3 Variants can occur in the N-terminal glutamic acid-rich protein (GARP) domain or in the channel domain. The GARP domain is important in rod photoreceptors, but its role in olfactory neurons is less clear; an alternatively spliced variant (CNGB1b), lacking this domain, is expressed in olfactory neurons in rats.…”