Decreased ACKR3 (CXCR7) function causes oculomotor synkinesis in mice and humans

Whitman, Mary C.; Miyake, Noriko; Nguyen, Elaine; Bell, Jéssica; Ruiz, Paola M. Matos; Chan, Wai Man; Gioia, Silvio Alessandro Di; Mukherjee, Nisha; Barry, Brenda J.; Bosley, Thomas M.; Khan, Arif O.; Engle, Elizabeth C.

doi:10.1093/hmg/ddz137

Cited by 13 publications

(15 citation statements)

References 56 publications

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“…The chromosome 2 duplication at 2p11.2 was present in 1.7% of patients with exotropia (4 of 234; P = .40), a similar proportion to the 1.4% of patients with esotropia (23 of 1614) in whom it was previously reported and higher than the 0.1% of controls (4 of 3922) previously reported (difference, 1.6%; 95% CI, 0%-3.3%; P < .001) (Figure 1). 14 This corresponds to a substantially increased exotropia risk (odds ratio [OR], 17.0; 95% CI, 4.9-58.7), similar to the risk for esotropia (OR, 14.2; 95% CI, 5.4-38.1).…”

Section: Resultsmentioning

confidence: 95%

“…Duplications were identified using digital droplet polymerase chain reaction (PCR; ddPCR [Bio-Rad]), 15 using the same probes used to confirm these CNVs in individuals with esotropia. 14 The probes were designed using a proprietary algorithm of Bio-Rad Laboratories. Locations of the probes were hg38|chr2:87,490,581-87,490,703, hg38|chr4:25,559,793-25,559,915, and hg38| chr10:46,449,597-46,449,719.…”

Section: Digital Droplet Polymerase Chain Reactionmentioning

confidence: 99%

“…[11][12][13] In a previous study, we identified 3 rare, recurrent duplications that increase the risk of esotropia in White populations. 14 The duplications include a 23kb duplication on chromosome 4 (hg38|4:25,554,985-25,578,843) that includes 1 long noncoding RNA (lncRNA); a 464kb duplication on chromosome 2 (hg38|2:87,201,554-87,665,840) that includes 1 ln-cRNA and 1 microRNA; and a 344kb duplication on chromosome 10 (hg38|10:46,172,086-46,516,407) that includes 2 lncRNAs and 3 protein-coding genes. The duplications were found in individuals with accommodative, nonaccommodative, and infantile esotropia.…”

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confidence: 99%

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Presence of Copy Number Variants Associated With Esotropia in Patients With Exotropia

Martinez Sanchez,

Chan,

MacKinnon

et al. 2024

JAMA Ophthalmol

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ImportanceStrabismus is a common ocular disorder of childhood. There is a clear genetic component to strabismus, but it is not known if esotropia and exotropia share genetic risk factors.ObjectiveTo determine whether genetic duplications associated with esotropia are also associated with exotropia.Design, Setting, and ParticipantsThis was a cross-sectional study conducted from November 2005 to December 2023. Individuals with constant or intermittent exotropia of any magnitude or a history of surgery for exotropia were recruited from pediatric ophthalmic practices. Data were analyzed from March to December 2023.ExposureGenetic duplication.Main Outcomes and MeasuresPresence of genetic duplications at 2p11.2, 4p15.2, and 10q11.22 assessed by digital droplet polymerase chain reaction. Orthoptic measurements and history of strabismus surgery were performed.ResultsA total of 234 individuals (mean [SD] age, 19.5 [19.0] years; 127 female [54.3%]) were included in this study. The chromosome 2 duplication was present in 1.7% of patients with exotropia (4 of 234; P = .40), a similar proportion to the 1.4% of patients with esotropia (23 of 1614) in whom it was previously reported and higher than the 0.1% of controls (4 of 3922) previously reported (difference, 1.6%; 95% CI, 0%-3.3%; P &lt; .001). The chromosome 4 duplication was present in 3.0% of patients with exotropia (7 of 234; P = .10), a similar proportion to the 1.7% of patients with esotropia (27 of 1614) and higher than the 0.2% of controls (6 of 3922) in whom it was previously reported (difference, 2.8%; 95% CI, 0.6%-5.0%; P &lt; .001). The chromosome 10 duplication was present in 6.0% of patients with exotropia (14 of 234; P = .08), a similar proportion to the 4% of patients with esotropia (64 of 1614) and higher than the 0.4% of controls (18 of 3922) in whom it was previously reported (difference, 5.6%; 95% CI, 2.5%-8.6%; P &lt; .001). Individuals with a duplication had higher mean (SD) magnitude of deviation (31 [13] vs 22 [14] prism diopters [PD]; difference, 9 PD; 95% CI, 1-16 PD; P = .03), were more likely to have constant (vs intermittent) exotropia (70% vs 29%; difference, 41%; 95% CI, 20.8%-61.2%; P &lt; .001), and had a higher rate of exotropia surgery than those without a duplication (58% vs 34%; difference, 24%; 95% CI, 3%-44%; P = .02).Conclusions and RelevanceIn this cross-sectional study, results suggest that the genetic duplications on chromosomes 2, 4, and 10 were risk factors for exotropia as well as esotropia. These findings support the possibility that esotropia and exotropia have shared genetic risk factors. Whether esotropia or exotropia develops in the presence of these duplications may be influenced by other shared or independent genetic variants or by environmental factors.

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Section: Resultsmentioning

confidence: 95%

Section: Digital Droplet Polymerase Chain Reactionmentioning

confidence: 99%

mentioning

confidence: 99%

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Presence of Copy Number Variants Associated With Esotropia in Patients With Exotropia

Martinez Sanchez,

Chan,

MacKinnon

et al. 2024

JAMA Ophthalmol

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“…Whole-mount E13.5, 14.5, and E15.5 embryos were prepared using a modified version of the previously described iDISCO+ protocol ( Renier et al, 2014 ; Whitman et al, 2019 ). Embryos were first collected and fixed overnight in 4% paraformaldehyde at 4°C, washed with PBS, dehydrated through a graded methanol series, bleached overnight in 5% H 2 O 2 in methanol, rehydrated through a graded methanol series, and washed in PBS with 2% Triton-X.…”

Section: Methodsmentioning

confidence: 99%

TWIST1, a gene associated with Saethre-Chotzen syndrome, regulates extraocular muscle organization in mouse

Whitman

Gilette

Bell

et al. 2022

Developmental Biology

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“…Interestingly, ACKR3/ CXCR7 was linked to myopia in a mapped region on chromosome 2q37 (Figure 8) (Schache et al, 2009). A few mutations in ACKR3 have been shown to cause oculomotor synkinesis, characterized by involuntary eye movements in mouse and humans (Whitman et al, 2019). CACNA1S (MIM# 114208), coding for the L-type voltage-dependent calcium channel, alpha-1S subunit, is required for normal skeletal and cardiac muscle function (Elbaz et al, 1995)).…”

Section: Bdnf (Mim# 113505) Encoding Brain-derived Neurotrophic Facto...mentioning

confidence: 99%

Shedding light on myopia by studying complete congenital stationary night blindness

Zeitz¹,

Roger²,

Michiels³

et al. 2022

Acta Ophthalmologica

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Purpose: Myopia is the most common eye disorder, caused by heterogeneous genetic and environmental factors. Rare inherited retinal disorders are often associated with high myopia. Genes implicated in myopia encode proteins involved in eye morphogenesis, extracellular matrix organization, visual perception, circadian rhythms, and retinal signalling. Differentially expressed genes (DEGs) identified in animal models mimicking myopia are helpful in suggesting candidate genes implicated in human myopia. Complete congenital stationary night blindness (cCSNB) in humans and animal models represents an ON‐bipolar cell signal transmission defect and is also associated with high myopia. The purpose of this work was to identify the molecular cause of myopia present in cCSNB. Methods: A whole transcriptome sequencing (RNA‐seq) approach was performed using retina from three mouse lines with cCSNB, Gpr179−/−, Lrit3−/− and Grm6−/− and the expression data compared to data of age‐matched wild‐type littermates (n = 5). DEGs with fold changes of at least 1.2, p‐values of ≤0.01, an expression value of at least 5 transcripts per million reads and appearing in at least two cCSNB mouse lines were investigated in detail. A meta‐analysis was performed by (a) comparing our data with published transcriptome data from purified retinal cells and single cell RNA‐Seq data, (b) pathway analyses, (c) myopia databases and publications concerning their role in normal vision. Several of the DEGs were validated by RT‐qPCR experiments and analysed by western blot and immunolocalization studies. Results: More than 50 DEGs were found in at least two cCSNB mouse lines. Expression of those was found in different retinal cell types. The difference in expression was independent of the number of nuclei present in wild‐type and mutant inner retina. Pathway analysis revealed that mitogen‐activated protein kinase pathways, synaptic signalling, G protein‐coupled receptor ligand binding pathways, and proteins implicated in eye, endoderm and connective tissue development were affected in cCSNB. More than half of the genes were already associated with myopia. Conclusions: Our study reveals DEGs in all retinal cell types of cCSNB models, previously associated with myopia and novel candidates. These studies combined with pathway analyses provide the basis for the development of pharmacological and optical myopia therapies.

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Decreased ACKR3 (CXCR7) function causes oculomotor synkinesis in mice and humans

Cited by 13 publications

References 56 publications

Presence of Copy Number Variants Associated With Esotropia in Patients With Exotropia

Presence of Copy Number Variants Associated With Esotropia in Patients With Exotropia

TWIST1, a gene associated with Saethre-Chotzen syndrome, regulates extraocular muscle organization in mouse

Shedding light on myopia by studying complete congenital stationary night blindness

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