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Microphthalmia is a significant eye defect owing to its profound effects on visual acuity. Microphthalmia accounts for 3.2%–11.2% of blind children. To date, there has been no cure for this disease. In this study, we aimed to identify microphthalmia-like mutant mouse and study its growth and development. In this study, we identified mutant mice exhibiting eye abnormalities using a forward genetics approach in a C57BL/6J cohort. To identify ocular characteristics of the mutant mouse, we conducted systematic evaluations including basic measurements (body length, body weight, and palpebral fissure width), optical coherence tomography (OCT), optomotor response (OMR), and hematoxylin-eosin (H&E) staining. At early developmental stages, there are notable differences in body length and weight between mutant and normal mice. Mutant mice displayed microphthalmia-like phenotypes, characterized by significantly reduced eyeball and lens sizes as well as decreased anterior chamber depth compared to wild-type controls. Visual impairment was evident in the mutant mice. Mutant mice exhibited rosette-like structures in the retina without impacting other organs of the body. Overall, these results support microphthalmia-like mutant mouse as a valuable tool for studying this congenital ocular malformation.

Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions. We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGUeye) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants. Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease. Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants.

Disturbances in the morphology and function of mitochondria cause neurological diseases, which can affect the central and peripheral nervous system. The i ‐AAA protease YME1L ensures mitochondrial proteostasis and regulates mitochondrial dynamics by processing of the dynamin‐like GTPase OPA1. Mutations in YME1L cause a multi‐systemic mitochondriopathy associated with neurological dysfunction and mitochondrial fragmentation but pathogenic mechanisms remained enigmatic. Here, we report on striking cell‐type‐specific defects in mice lacking YME1L in the nervous system. YME1L‐deficient mice manifest ocular dysfunction with microphthalmia and cataracts and develop deficiencies in locomotor activity due to specific degeneration of spinal cord axons, which relay proprioceptive signals from the hind limbs to the cerebellum. Mitochondrial fragmentation occurs throughout the nervous system and does not correlate with the degenerative phenotype. Deletion of Oma1 restores tubular mitochondria but deteriorates axonal degeneration in the absence of YME1L, demonstrating that impaired mitochondrial proteostasis rather than mitochondrial fragmentation causes the observed neurological defects. Synopsis Novel mouse models demonstrate the importance of mitochondrial proteostasis for eye development and axonal maintenance in the spinal cord. Loss of the mitochondrial protease YME1L induces cell‐specific neurodegeneration independently of respiratory chain defects and mitochondria fragmentation. Mice lacking YME1L in the nervous system (NYKO mice) show microphthalmia with cataracts and late‐onset degeneration of spinal cord axons involved in proprioception. YME1L regulates anterograde axonal transport of mitochondria in cultured neurons. Loss of the mitochondrial protease OMA1 in NYKO mice suppresses aberrant OPA1 processing and mitochondrial fragmentation, but not neurodegeneration in absence of YME1L. OMA1 exerts pro‐survival functions and delays the degeneration of YME1L‐ deficient neurons. Graphical Abstract Novel mouse models demonstrate the importance of mitochondrial proteostasis for eye development and axonal maintenance in the spinal cord. Loss of the mitochondrial protease YME1L induces cell‐specific neurodegeneration independently of respiratory chain defects and mitochondria fragmentation.

Despite the identification of many genes involved in developmental eye phenotypes, a large percentage of families lack genetic diagnoses, suggesting novel mechanisms remain to be discovered. Large deletions of 16p11.2, 3p14 or 19p13.11 regions involving transcription factors MAZ, FOXP1 and SIN3B, correspondingly, along with other genes, have been previously reported in individuals with neurodevelopmental and variable other features, including ocular coloboma and/or microphthalmia; recently, intragenic variants in FOXP1 and SIN3B have also been shown to cause neurodevelopmental phenotypes, with developmental eye defects reported in a small number of individuals with FOXP1 variants. Through exome sequencing analysis we identified novel splicing variants in MAZ and SIN3B, and a recurrent nonsense allele in FOXP1 in unrelated families affected with colobomatous microphthalmia, all with predicted loss-of-function effects; additionally, we report two new families with coloboma and 16p11.2 genomic deletions including MAZ, one de novo and another inherited from an affected parent. These findings provide further support for a role for FOXP1 in structural eye phenotypes, expanding its spectrum to include colobomatous microphthalmia, and suggest a role for MAZ and SIN3B in human eye development and disease.

Microphthalmia and coloboma are structural malformations of the eyes that arise from defective morphogenesis and are among the most severe defects associated with paediatric blindness. Frizzled class receptor 5 (FZD5) is a Wnt receptor expressed in the developing eye, and individuals with variants in FZD5 exhibit microphthalmia/coloboma, supporting a role for this receptor in human eye formation. Here, we show that zebrafish fzd5 mutants homozygous for complete loss-of-function or predicted dominant-negative alleles display no obvious eye defects during embryogenesis. Rather, they develop eye defects comparable to those described in humans only upon simultaneous abrogation of additional genes associated with ocular malformations. Thus, eye development can occur normally in the absence of Fzd5 in zebrafish, but mutants are sensitised to developing eye malformations. By exploiting the sensitised nature of the fzd5 mutants, we further identified angio-associated migratory cell protein (aamp) as a novel gene involved in eye morphogenesis. Overall, our study confirms the importance of considering multiple genetic contributions when searching for the molecular aetiology of ocular malformations in humans.

Congenital eye malformations are uncommon and in some dog breeds, there is no evidence of their occurrence. This report aimed to describe the clinical and ultrasonographic findings of complex microphthalmia in Central Asian Shepherd dogs. Three 2‐month‐old female Central Asian Shepherd puppies from two litters were referred to our teaching hospital with the owner's complaint of eye abnormalities since birth. The puppies were alert on clinical examination, the vital signs were normal, and no other structural abnormalities were observed. In the ophthalmological assessments of all three dogs, the globe appeared bilaterally small and sunken in the orbit. In the ultrasound of the puppies’ eyes, the lens thickness and axial length of the globe were greater and less than the values measured in the eyes of a healthy puppy of the same age and breed, respectively. Moreover, in all three puppies, the lenses were located in the vitreous chamber and displaced perpendicular to their natural axis. On the basis of this, bilateral complex microphthalmia and congenital ectopia lentis, two ocular malformations of unclear etiology, were diagnosed. Due to the possibility of an association between such malformations and a high grade of inbreeding in kennels, as well as environmental and genetic factors, these conditions can be limited by breeding efforts and pre‐breeding screening plans. Here is a description of the main ultrasound findings in three Central Asian Shepherd puppies with complex microphthalmia, a rare congenital ocular malformation, compared to a healthy puppy of the same breed, age and sex. Accordingly, in dogs with complex microphthalmia, the mean ± standard deviation of axial length (AL) of the globe was shorter, and the vitreous chamber depth (VCD) and lens thickness (LT) were greater than those of the healthy dog. Surprisingly, all patients had ectopia lentis (EL).

Colobomatous microphthalmia is a potentially blinding congenital ocular malformation that can present either in isolation or together with other syndromic features. Despite a strong genetic component to disease, many cases lack a molecular diagnosis. We describe an autosomal dominant oculo-vertebral-renal (OVR) syndrome in six independent families characterized by colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities. Genome sequencing identified six rare variants in the orphan nuclear receptor gene NR6A1 in these families. We performed in silico, cellular, and zebrafish experiments to demonstrate the NR6A1 variants were pathogenic or likely pathogenic for OVR syndrome. Knockdown of either or both zebrafish paralogs of NR6A1 results in abnormal eye, kidney, and somite development, which was rescued by wild-type but not variant NR6A1 mRNA. Illustrating the power of genomic ascertainment in medicine, our study establishes NR6A1 as a critical factor in eye, kidney, and vertebral development, and a pleiotropic gene responsible for OVR syndrome. Colobomatous microphthalmia often lacks a genetic diagnosis despite its developmental complexity. Here, the authors show that rare variants in NR6A1 cause a syndromic form with eye, kidney, and vertebral defects, supported by zebrafish functional validation.

This study describes genomic findings among individuals with both orofacial clefts (OC) and microphthalmia/anophthalmia/coloboma (MAC) recorded in the Brazilian Database on Craniofacial Anomalies (BDCA). Chromosomal microarray analysis (CMA) and Whole Exome Sequencing (WES) were performed in 17 individuals with OC-MAC. Clinical interpretation of molecular findings was based on data available at the BDCA and on re-examination. No copy number variants (CNVs) classified as likely pathogenic or pathogenic were detected by CMA. WES allowed a conclusive diagnosis in six individuals (35.29%), two of them with variants in the CHD7 gene, and the others with variants in the TFAP2A , POMT1 , PTPN11 , and TP63 genes with the following syndromes: CHARGE, CHD7 -spectrum, Branchiooculofacial, POMT1 -spectrum, LEOPARD, and ADULT. Variants of uncertain significance (VUS) possibly associated to the phenotypes were found in six other individuals. Among the individuals with VUSes, three individuals presented variants in genes associated to defects of cilia structure and/or function, including DYNC2H1 , KIAA0586 , WDR34 , INTU , RPGRIP1L , KIF7 , and LMNA . These results show that WES was the most effective molecular approach for OC-MAC in this cohort. This study also reinforces the genetic heterogeneity of OC-MAC, and the importance of genes related to ciliopathies in this phenotype.

Nanophthalmos is characterised by shorter posterior and anterior segments of the eye, with a predisposition towards high hyperopia and primary angle-closure glaucoma. Variants in TMEM98 have been associated with autosomal dominant nanophthalmos in multiple kindreds, but definitive evidence for causation has been limited. Here we used CRISPR/Cas9 mutagenesis to recreate the human nanophthalmos-associated TMEM98 p.(Ala193Pro) variant in mice. The p.(Ala193Pro) variant was associated with ocular phenotypes in both mice and humans, with dominant inheritance in humans and recessive inheritance in mice. Unlike their human counterparts, p.(Ala193Pro) homozygous mutant mice had normal axial length, normal intraocular pressure, and structurally normal scleral collagen. However, in both homozygous mice and heterozygous humans, the p.(Ala193Pro) variant was associated with discrete white spots throughout the retinal fundus, with corresponding retinal folds on histology. This direct comparison of a TMEM98 variant in mouse and human suggests that certain nanophthalmos-associated phenotypes are not only a consequence of a smaller eye, but that TMEM98 may itself play a primary role in retinal and scleral structure and integrity.

X-chromosome inactivation (XCI) is an essential epigenetic process in female mammalian development. Although cell-based studies suggest the potential importance of the Ftx long non-protein-coding RNA (lncRNA) in XCI, its physiological roles in vivo remain unclear. Here we show that targeted deletion of X-linked mouse Ftx lncRNA causes eye abnormalities resembling human microphthalmia in a subset of females but rarely in males. This inheritance pattern cannot be explained by X-linked dominant or recessive inheritance, where males typically show a more severe phenotype than females. In Ftx -deficient mice, some X-linked genes remain active on the inactive X, suggesting that defects in random XCI in somatic cells cause a substantially female-specific phenotype. The expression level of Xist , a master regulator of XCI, is diminished in females homozygous or heterozygous for Ftx deficiency. We propose that loss-of- Ftx lncRNA abolishes gene silencing on the inactive X chromosome, leading to a female microphthalmia-like phenotype. Although Ftx lncRNA has been linked to X-chromosome inactivation, its physiological roles in vivo remain unclear. Here the authors show that deletion of mouse Ftx causes eye abnormalities similar to human microphthalmia in a subset of female mice but rarely in males and provide evidence that Ftx plays a role in gene silencing on the inactive X chromosome.