Congenital Microcoria: Clinical Features and Molecular Genetics

Abstract

Iris integrity is required to regulate both the amount of light reaching the retina and intraocular pressure (IOP), with elevated IOP being a major risk factor for glaucoma. Congenital microcoria (MCOR) is an extremely rare, autosomal dominant disease affecting iris development and hindering both of these functions. It is characterized by absent or underdeveloped dilator muscle fibers and immaturity of the iridocorneal angle—where the aqueous humor is drained—which play a central role in IOP regulation. The dilator muscle anomaly is manifested in pinhole pupils (<2 mm) and thin transilluminable irises, causing both hemeralopia and photoaversion. Axial myopia and juvenile open-angle glaucoma are very frequent (80% and 30% of all cases, respectively). It has been suggested that the immaturity of the chamber angle contributes to glaucoma, and myopia has been ascribed to photoaversion and elevated IOP. Though possible, these mechanisms are insufficient. The disease has been tied to chromosome 13q32.1 structural variations. In addition to compromising iris development, modification of the 13q32.1 architecture could alter signaling pathways for axial ocular length and IOP regulation. Here, we summarize the clinical, histological, and molecular features of this disease, and we discuss the possible etiology of associated anomalies.

Modeling the critical MCOR-causing deletion in mouse unveils aberrant Sox21 expression in developing and adult iris and ciliary body, and implicates Tgf β 2 in MCOR-associated glaucoma and myopia

“…While the iris phenotype in the mutant mouse is minimal, it is noteworthy that we observed a reduced expression of desmin in the iris of newborn mutant mice. This finding aligns with studies on iris anatomy, which report the absence or severe reduction of desmin fibers in the anterior epithelium of microcoric irises (as reviewed in Angée et al 2021).…”

“…TAD2 that comprises the original 1 Mb TAD can be broken down into three interacting sub-TADs of 0.2 (TAD2.1), 0.5 (TAD2.2), and 0.2 (TAD2.3) Mb, respectively. Remarkably, all documented deletions associated with MCOR (reviewed by Angée et al 3 ), exhibit modifications at the interface between TAD2.1 and TAD2.2, along with alterations within the regions of both TADs that engage in mutual interactions ( Figure 1A and 1B ). This underscores the significance of the boundary between TAD2.1 and TAD2.2 and emphasizes the intricate interplay within these topologically associating domains in the context of MCOR.…”

Modeling the critical MCOR-causing deletion in mouse unveils aberrant Sox21 expression in developing and adult iris and ciliary body, and implicates Tgf β 2 in MCOR-associated glaucoma and myopia

“…While the iris phenotype in the mutant mouse is minimal, it is noteworthy that we observed a reduced expression of desmin in the iris of newborn mutant mice. This finding aligns with studies on iris anatomy, which report the absence or severe reduction of desmin fibers in the anterior epithelium of microcoric irises (as reviewed in Angée et al 2021).…”

“…TAD2 that comprises the original 1 Mb TAD can be broken down into three interacting sub-TADs of 0.2 (TAD2.1), 0.5 (TAD2.2), and 0.2 (TAD2.3) Mb, respectively. Remarkably, all documented deletions associated with MCOR (reviewed by Angée et al 3 ), exhibit modifications at the interface between TAD2.1 and TAD2.2, along with alterations within the regions of both TADs that engage in mutual interactions ( Figure 1A and 1B ). This underscores the significance of the boundary between TAD2.1 and TAD2.2 and emphasizes the intricate interplay within these topologically associating domains in the context of MCOR.…”

The novel ITPR1 p.Phe2566Ser variant impairs IP 3 R1‐mediated Ca 2+ release and is associated with ataxia and miosis

“…Unlike previously reported ataxia-miosis cases [2,3], none exhibited intellectual disability or dysmorphism (Tables S1 andS2). The iris phenotype of the index, however, closely resembled that described by Chesneau et al [3], with a thin dilator muscle without iris transillumination, distinguishing it from congenital microcoria [4]. Detailed clini-cal information can be found in the Supporting Information.…”

ITPR1: The missing gene in miosis–ataxia syndrome?

“…This malformation of the iris is characterized by the partial or total absence of the dilator muscle, which also manifests with congenital miosis. However, it is associated with iris hypopigmentation and transillumination (Angée et al, 2021), findings that were absent in our patient. Microcoria has been linked to structural variations in chromosome 13q32.1 in several families (Angée et al, 2021).…”

“…However, it is associated with iris hypopigmentation and transillumination (Angée et al, 2021), findings that were absent in our patient. Microcoria has been linked to structural variations in chromosome 13q32.1 in several families (Angée et al, 2021). Of note, the 180 k custom array CGH ruled out any CNV within this region.…”

Modeling the critical MCOR-causing deletion in mouse unveils aberrant Sox21 expression in developing and adult iris and ciliary body, and implicates Tgf β 2 in MCOR-associated glaucoma and myopia

“…While the iris phenotype in the mutant mouse is minimal, it is noteworthy that we observed a reduced expression of desmin in the iris of newborn mutant mice. This finding aligns with studies on iris anatomy, which report the absence or severe reduction of desmin fibers in the anterior epithelium of microcoric irises (as reviewed in Angée et al 2021).…”

“…TAD2 that comprises the original 1 Mb TAD can be broken down into three interacting sub-TADs of 0.2 (TAD2.1), 0.5 (TAD2.2), and 0.2 (TAD2.3) Mb, respectively. Remarkably, all documented deletions associated with MCOR (reviewed by Angée et al 3 ), exhibit modifications at the interface between TAD2.1 and TAD2.2, along with alterations within the regions of both TADs that engage in mutual interactions ( Figure 1A and 1B ). This underscores the significance of the boundary between TAD2.1 and TAD2.2 and emphasizes the intricate interplay within these topologically associating domains in the context of MCOR.…”

The novel ITPR1 p.Phe2566Ser variant impairs IP 3 R1‐mediated Ca 2+ release and is associated with ataxia and miosis

“…Unlike previously reported ataxia-miosis cases [2,3], none exhibited intellectual disability or dysmorphism (Tables S1 andS2). The iris phenotype of the index, however, closely resembled that described by Chesneau et al [3], with a thin dilator muscle without iris transillumination, distinguishing it from congenital microcoria [4]. Detailed clini-cal information can be found in the Supporting Information.…”

ITPR1: The missing gene in miosis–ataxia syndrome?

“…This malformation of the iris is characterized by the partial or total absence of the dilator muscle, which also manifests with congenital miosis. However, it is associated with iris hypopigmentation and transillumination (Angée et al, 2021), findings that were absent in our patient. Microcoria has been linked to structural variations in chromosome 13q32.1 in several families (Angée et al, 2021).…”

“…However, it is associated with iris hypopigmentation and transillumination (Angée et al, 2021), findings that were absent in our patient. Microcoria has been linked to structural variations in chromosome 13q32.1 in several families (Angée et al, 2021). Of note, the 180 k custom array CGH ruled out any CNV within this region.…”

Modeling the critical MCOR-causing deletion in mouse unveils aberrant Sox21 expression in developing and adult iris and ciliary body, and implicates Tgf β 2 in MCOR-associated glaucoma and myopia

“…While the iris phenotype in the mutant mouse is minimal, it is noteworthy that we observed a reduced expression of desmin in the iris of newborn mutant mice. This finding aligns with studies on iris anatomy, which report the absence or severe reduction of desmin fibers in the anterior epithelium of microcoric irises (as reviewed in Angée et al 2021).…”

“…TAD2 that comprises the original 1 Mb TAD can be broken down into three interacting sub-TADs of 0.2 (TAD2.1), 0.5 (TAD2.2), and 0.2 (TAD2.3) Mb, respectively. Remarkably, all documented deletions associated with MCOR (reviewed by Angée et al 3 ), exhibit modifications at the interface between TAD2.1 and TAD2.2, along with alterations within the regions of both TADs that engage in mutual interactions ( Figure 1A and 1B ). This underscores the significance of the boundary between TAD2.1 and TAD2.2 and emphasizes the intricate interplay within these topologically associating domains in the context of MCOR.…”

The novel ITPR1 p.Phe2566Ser variant impairs IP 3 R1‐mediated Ca 2+ release and is associated with ataxia and miosis

“…Unlike previously reported ataxia-miosis cases [2,3], none exhibited intellectual disability or dysmorphism (Tables S1 andS2). The iris phenotype of the index, however, closely resembled that described by Chesneau et al [3], with a thin dilator muscle without iris transillumination, distinguishing it from congenital microcoria [4]. Detailed clini-cal information can be found in the Supporting Information.…”

ITPR1: The missing gene in miosis–ataxia syndrome?

“…This malformation of the iris is characterized by the partial or total absence of the dilator muscle, which also manifests with congenital miosis. However, it is associated with iris hypopigmentation and transillumination (Angée et al, 2021), findings that were absent in our patient. Microcoria has been linked to structural variations in chromosome 13q32.1 in several families (Angée et al, 2021).…”

“…However, it is associated with iris hypopigmentation and transillumination (Angée et al, 2021), findings that were absent in our patient. Microcoria has been linked to structural variations in chromosome 13q32.1 in several families (Angée et al, 2021). Of note, the 180 k custom array CGH ruled out any CNV within this region.…”