Mutations in the polyglutamylase gene TTLL5, expressed in photoreceptor cells and spermatozoa, are associated with cone-rod degeneration and reduced male fertility.

Hereditary retinal degenerations encompass a group of genetic diseases characterized by extreme clinical variability. Following next-generation sequencing and autozygome-based screening of patients presenting with a peculiar, recessive form of cone-dominated retinopathy, we identified five homozygous variants [p.(Asp594fs), p.(Gln117*), p.(Met712fs), p.(Ile756Phe), and p.(Glu543Lys)] in the polyglutamylase-encoding gene TTLL5, in eight patients from six families. The two male patients carrying truncating TTLL5 variants also displayed a substantial reduction in sperm motility and infertility, whereas those carrying missense changes were fertile. Defects in this polyglutamylase in humans have recently been associated with cone photoreceptor dystrophy, while mouse models carrying truncating mutations in the same gene also display reduced fertility in male animals. We examined the expression levels of TTLL5 in various human tissues and determined that this gene has multiple viable isoforms, being highly expressed in testis and retina. In addition, antibodies against TTLL5 stained the basal body of photoreceptor cells in rat and the centrosome of the spermatozoon flagellum in humans, suggesting a common mechanism of action in these two cell types. Taken together, our data indicate that mutations in TTLL5 delineate a novel, allele-specific syndrome causing defects in two as yet pathogenically unrelated functions, reproduction and vision.

Loss of the metalloprotease ADAM9 leads to cone-rod dystrophy in humans and retinal degeneration in mice.

Cone-rod dystrophy (CRD) is an inherited progressive retinal dystrophy affecting the function of cone and rod photoreceptors. By autozygosity mapping, we identified null mutations in the ADAM metallopeptidase domain 9 (ADAM9) gene in four consanguineous families with recessively inherited early-onset CRD. We also found reduced photoreceptor responses in Adam9 knockout mice, previously reported to be asymptomatic. In 12-month-old knockout mice, photoreceptors appear normal, but the apical processes of the retinal pigment epithelium (RPE) cells are disorganized and contact between photoreceptor outer segments (POSs) and the RPE apical surface is compromised. In 20-month-old mice, there is clear evidence of progressive retinal degeneration with disorganized POS and thinning of the outer nuclear layer (ONL) in addition to the anomaly at the POS-RPE junction. RPE basal deposits and macrophages were also apparent in older mice. These findings therefore not only identify ADAM9 as a CRD gene but also identify a form of pathology wherein retinal disease first manifests at the POS-RPE junction.

Homozygous FOXE3 mutations cause non-syndromic, bilateral, total sclerocornea, aphakia, microphthalmia and optic disc coloboma.

PURPOSE: To investigate the genetic basis of recessively-inherited congenital, non syndromic, bilateral, total sclerocornea in two consanguineous pedigrees, one from the Punjab province of Pakistan and the other from the Tlaxcala province of Mexico. METHODS: Ophthalmic examinations were conducted on each family member to confirm their diagnosis and magnetic resonance imaging (MRI) or ultrasonography of the eyes was performed on some family members. Genomic DNA was analyzed by homozygosity mapping using the Affymetrix 6.0 SNP array and linkage was confirmed with polymorphic microsatellite markers. Candidate genes were sequenced. RESULTS: A diagnosis of autosomal recessive sclerocornea was established for 7 members of the Pakistani and 8 members of the Mexican pedigrees. In the Pakistani family we established linkage to a region on chromosome 1p that contained Forkhead Box E3 (FOXE3), a strong candidate gene since FOXE3 mutations had previously been associated with various anterior segment abnormalities. Sequencing FOXE3 identified the previously reported nonsense mutation, c.720C>A, p.C240X, in the Pakistani pedigree and a novel missense mutation which disrupts an evolutionarily conserved residue in the forkhead domain, c.292T>C, p.Y98H, in the Mexican pedigree. Individuals with heterozygous mutations had no ocular abnormalities. MRI or ultrasonography confirmed that the patients with sclerocornea were also aphakic, had microphthalmia and some had optic disc coloboma. CONCLUSIONS: This is the fourth report detailing homozygous FOXE3 mutations causing anterior segment abnormalities in human patients. Previous papers have emphasized aphakia and microphthalmia as the primary phenotype, but we find that the initial diagnosis - and perhaps the only one possible in a rural setting - is one of non-syndromic, bilateral, total sclerocornea. Dominantly inherited anterior segment defects have also been noted in association with heterozygous FOXE3 mutations. However the absence of any abnormalities in the FOXE3 heterozygotes described suggests that genetic background and environmental factors plays a role in the penetrance of the mutant allele.

Ciliary Body and Iris Metastases With Anterior Chamber Angle Infiltration: A Rare Complication From Invasive Ductal Breast Cancer.

A 54-year-old woman who presented with photopsia was found to have elevated intraocular pressure in both eyes and optic disc cupping in the right eye. Angle infiltration was noted on gonioscopy. She was previously been diagnosed with metastatic breast cancer. This case report describes a rare case of glaucoma as a complication of ciliary body and iris metastases secondary to invasive ductal breast cancer.

Myocilin Gly252Arg mutation and glaucoma of intermediate severity in Caucasian individuals.

OBJECTIVE: To determine the phenotype of an Australian pedigree with the myocilin (MYOC) Gly252Arg mutation, comparing it with other pedigrees carrying the same mutation. METHODS: All recruited subjects underwent a comprehensive clinical examination, including optic disc assessment, applanation tonometry, and visual field measurement. Mutation analysis was performed through direct sequencing. Haplotype analysis was performed using microsatellite markers around the MYOC gene. RESULTS: Eight Gly252Arg mutation carriers with glaucoma were identified from the same pedigree. Carriers' mean +/- SD age at diagnosis was 46.3 +/- 11.4 years (range, 31-60 years). Highest recorded intraocular pressure ranged from 27 to 42 mm Hg (mean +/- SD, 32.4 +/- 5.6 mm Hg). Cup-disc ratios in the worst eye ranged from 0.6 to 0.9. Six of the 8 individuals had undergone filtration surgery. A common founding haplotype between MY5 and D1S218 was found for Caucasian individuals tested with this mutation. One subject was compound heterozygotic for the MYOC Gly252Arg mutation and a novel MYOC Gly244Val variant. CONCLUSIONS: Although a common founder for Gly252Arg across Caucasian subjects was found, the phenotype from this Australian MYOC mutation-carrying pedigree is less severe than previously described. The severity of glaucoma caused by the Gly252Arg mutation may be similar to the Thr377Met MYOC mutation, yet is more severe than the most common Gln368Stop mutation. CLINICAL RELEVANCE: Since its implication in glaucoma, much work has been performed investigating the clinical features of MYOC-related glaucoma. Given the strong genotype-phenotype correlations with MYOC disease-causing variants, health care professionals armed with such molecular information are able to accurately counsel patients on their likely disease course. Our work suggests that the disease associated with MYOC Gly252Arg is less severe than previously described in other pedigrees with this specific mutation.

Chorioretinal folds in a patient with multiple myeloma treated with stem cell transplant.

PURPOSE: To report an unusual case of bilateral choroidal folds related to multiple myeloma. METHODS: In this case report, fundus photography, fundus fluorescein angiography, fundus autofluorescence, and B-ultrasonography were used to assess posterior segment changes. RESULTS: A 55-year-old woman with history of multiple myeloma was found to have abnormal fundi. Clinical examination and investigations confirmed chorioretinal folds, which was considered to be related to myeloma. Close monitoring ensued for 2 years with no significant changes. Subsequently, she was treated with stem cell transplant for myeloma, which resulted in remission of her disease. She was also noted to have marked improvement of chorioretinal folds within 1 year. Visual function remained normal throughout the follow-up period. CONCLUSIONS: Multiple myeloma can infiltrate choroidal tissue, resulting in chorioretinal folds. Stem cell transplant was associated with significant reduction in paraprotein levels and choroidal folds.

Glaucoma surgery.

Glaucoma is a potentially blinding condition that cannot be easily defined. There are various types of glaucoma which may vary in symptoms from none at all to sudden pain and redness. There is a characteristic optic neuropathy, or damage to the optic nerve, which results in progressive loss of visual field. The most important risk factor is an increase in the intraocular pressure (IOP) secondary to a reduction in the drainage of aqueous fluid from the drainage pathways in the eye, the filtration angle (Kanski 2007, Allingham et al 2011).

Genotype-phenotype correlation for leber congenital amaurosis in Northern Pakistan.

OBJECTIVES: To report the genetic basis of Leber congenital amaurosis (LCA) in northern Pakistan and to describe the phenotype. METHODS: DNA from 14 families was analyzed using single-nucleotide polymorphism and microsatellite genotyping and direct sequencing to determine the genes and mutations involved. The history and examination findings from 64 affected individuals were analyzed to show genotype-phenotype correlation and phenotypic progression. RESULTS: Homozygous mutations were found in RPGRIP1 (4 families), AIPL1 and LCA5 (3 families each), and RPE65, CRB1, and TULP1 (1 family each). Six of the mutations are novel. An additional family demonstrated linkage to the LCA9 locus. Visual acuity, severe keratoconus, cataract, and macular atrophy were the most helpful features in predicting the genotype. Many of the phenotypic variables became more prevalent with increasing age. CONCLUSIONS: Leber congenital amaurosis in northern Pakistan is genetically heterogeneous. Mutations in RPGRIP1, AIPL1, and LCA5 accounted for disease in 10 of the 14 families. This study illustrates the differences in phenotype, for both the anterior and posterior segments, seen between patients with identical or different mutations in the LCA genes and also suggests that at least some of the phenotypic variation is age dependent. CLINICAL RELEVANCE: The LCA phenotype, especially one including different generations in the same family, may be used to refine a molecular diagnostic strategy.