Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA-protein interaction

Purpose: 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. Methods: 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. Results: 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. Conclusion: 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

Corneal opacities in the Hallermann-Streiff syndrome

We present six patients with typical Hallermann-Streiff syndrome. All have microphthalmia and were operated for congenital cataract. Three of the patients developed a severe glaucoma and one patient presented repeated uveal effusions. Five of our patients have the same pattern of corneal stromal opacities. The opacities are ill defined and bilateral; the stroma between the opacities is clear. The opacities are observed in two children around the age of 5. Follow up of 10 years did not reveal a manifest increase of the lesions. The authors believe that corneal stromal opacities are a feature of the Hallermann-Streiff syndrome and they would urge ophthalmologists to look for this

Low vision affects dynamic stability of gait

The objective of this study was to demonstrate specific differences in gait patterns between those with and without a visual impairment. We performed a biomechanical analysis of the gait pattern of young adults (27±13 years old) with a visual impairment (n=10) in an uncluttered environment and compared it to the gait pattern of age matched controls (n=20). Normally sighted adults were tested in a full vision and no vision condition. Differences are found in gait between both groups and both situations. Adults with a visual impairment walked with a shorter stride length (1.14±0.21m), less trunk flexion (4.55±5.14°) and an earlier plantar foot contact at heel strike (1.83±3.49°) than sighted individuals (1.39±0.08m; 11.07±4.01°; 5.10±3.53°). When sighted individuals were blindfolded (no vision condition) they showed similar gait adaptations as well as a slower walking speed (0.84±0.28ms -1), a lower cadence (96.88±13.71stepsmin -1) and limited movements of the hip (38.24±6.27°) and the ankle in the saggital plane (-5.60±5.07°) compared to a full vision condition (1.27±0.13ms -1; 110.55±7.09stepsmin -1; 45.32±4.57°; -16.51±6.59°).Results showed that even in an uncluttered environment vision is important for locomotion control. The differences between those with and without a visual impairment, and between the full vision and no vision conditions, may reflect a more cautious walking strategy and adaptive changes employed to use the foot to probe the ground for haptic exploration. © 2010 Elsevier B.V.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

'Saothrú na Gaeilge ar Nuachtáin Náisiúnta Bhéarla na hAoise seo Caite: Sop nó Solamar?

peer-reviewe

Congenital fixed dilated pupils due to ACTA2-multisystemic smooth muscle dysfunction syndrome

Congenital fixed dilated pupils (congenital mydriasis) is characterized by hypoplasia or aplasia of the iris muscles, with absence of iris between the collarette and pupillary border, creating a scalloped pupillary margin. This condition has been reported in a multisystemic smooth muscle cell dysfunction syndrome, combined with congenital patent ductus arteriosus, cerebrovascular disease (Moya-moya-like), coronary artery disease, thoracic aorta aneurysm, and dysfunction of smooth muscle cells in organs throughout the body. All affected individuals carry a p.R179H heterozygous mutation in the ACTA2 gene. We add to the ophthalmologic involvement with 3 more patients. Congenital fixed dilated pupils is a rare condition and should alert ophthalmologists to the possibility of the coexistence of systemic life-threatening disorders. 2014 by North American Neuro-Ophthalmology Society.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

SLC24A5 Mutations are associated with non-syndromic oculocutaneous albinism

SCOPUS: le.jinfo:eu-repo/semantics/publishe

Mutations in GRM6 Cause Autosomal Recessive Congenital Stationary Night Blindness with a Distinctive Scotopic 15-Hz Flicker Electroretinogram

PURPOSE: Congenital stationary night blindness (CSNB) is a group of nonprogressive retinal disorders characterized by impaired night vision that occurs in autosomal dominant, autosomal recessive, or X-linked forms. Autosomal recessive (ar)CSNB seems to be very rare. Mice lacking the metabotropic glutamate receptor 6 (Grm6) have a defect in signal transmission from the photoreceptors to ON-bipolar cells. In the current study, the human orthologue (GRM6) was screened as a likely candidate for arCSNB. METHODS: arCSNB individuals of five families were screened for mutations in GRM6. Subsequently, they were examined with standard and 15-Hz flicker electroretinography (ERG). These recordings were compared with those of patients with X-linked CSNB1. RESULTS: Affected individuals in three of five families carried either compound heterozygous or homozygous mutations in GRM6. Strikingly, all of them displayed a distinctive abnormality of the rod pathway signals on scotopic 15-Hz flicker ERG. CONCLUSIONS: The novel profile identified in this study suggests the existence of more than two rod pathways. The distinctive ERG feature was not observed in patients with X-linked CSNB1 and additional affected individuals with unknown molecular defect. These observations will help to discriminate autosomal recessive from X-linked recessive cases by ERG and molecular genetic analysis