A novel homozygous missense mutation p.P388S in TULP1 causes protein instability and retinitis pigmentosa.

Purpose: Retinitis pigmentosa (RP) is an inherited retinal disorder that results in the degeneration of photoreceptor cells, ultimately leading to severe visual impairment. We characterized a consanguineous family from Southern India wherein a 25 year old individual presented with night blindness since childhood. The purpose of this study was to identify the causative mutation for RP in this individual as well as characterize how the mutation may ultimately affect protein function. Methods: We performed a complete ophthalmologic examination of the proband followed by exome sequencing. The likely causative mutation was identified and modeled in cultured cells, evaluating its expression, solubility (both with western blotting), subcellular distribution, (confocal microscopy), and testing whether this variant induced endoplasmic reticulum (ER) stress (quantitative PCR [qPCR] and western blotting). Results: The proband presented with generalized and parafoveal retinal pigmented epithelium (RPE) atrophy with bone spicule-like pigmentation in the midperiphery and arteriolar attenuation. Optical coherence tomography scans through the macula of both eyes showed atrophy of the outer retinal layers with loss of the ellipsoid zone, whereas the systemic examination of this individual was normal. The proband's parents and sibling were asymptomatic and had normal funduscopic examinations. We discovered a novel homozygous p.Pro388Ser mutation in the tubby-like protein 1 (TULP1) gene in the individual with RP. In cultured cells, the P388S mutation does not alter the subcellular distribution of TULP1 or induce ER stress when compared to wild-type TULP1, but instead significantly lowers protein stability as indicated with steady-state and cycloheximide-chase experiments. Conclusions: These results add to the list of known mutations in TULP1 identified in individuals with RP and suggest a possible unique pathogenic mechanism in TULP1-induced RP, which may be shared among select mutations in TULP1.

A novel H395R mutation in MKKS/BBS6 causes retinitis pigmentosa and polydactyly without other findings of Bardet-Biedl or McKusick-Kaufman syndrome.

PURPOSE: To identify the causative mutation in two siblings from a consanguineous family in India with retinitis pigmentosa (RP) and polydactyly without other findings of Bardet-Biedl syndrome (BBS). We also performed functional characterization of the mutant protein to explore its role in this limited form of BBS. METHODS: The siblings underwent a thorough ophthalmological examination, including retinal optical coherence tomography (OCT) imaging, and an extensive physical examination with abdominal ultrasonography to characterize the disease phenotype. Next-generation sequencing (NGS) using a panel targeting retinal degeneration genes was performed on genomic DNA samples from the siblings and parents. Upon identification of the causative mutation, functional characterization was accomplished by performing protein-protein interaction studies in human embryonic kidney (HEK-293T) and human adult retinal pigmented epithelium (ARPE-19) cells. RESULTS: The two siblings showed signs of RP and polydactyly. The patients did not have truncal obesity, renal anomalies, hydrometrocolpos, congenital heart disease, or overt cognitive defects. NGS identified a homozygous c.1184A>G mutation in the MKKS/BBS6 gene in both patients resulting in a p.H395R substitution in the MKKS/BBS6 protein. This mutant protein decreased the interaction of MKKS/BBS6 with BBS12 but did so to a different extent in the HEK-293T versus ARPE-19 cells. Nonetheless, the effect of the H395R variant on disrupting interactions with BBS12 was not as profound as other reported MKKS/BBS6 mutations associated with syndromic RP. CONCLUSIONS: We identified a novel H395R substitution in MKKS/BBS6 that results in a unique phenotype of only RP and polydactyly. Our observations reaffirm the notion that mutations in MKKS/BBS6 cause phenotypic heterogeneity and do not always result in classic MKKS or BBS findings.

Orbital ectopic glial tissue in relation to medial rectus: a rare entity.

Heterotopic brain tissue is a rare entity and it is rarer still in the orbit. There have been very few case reports of orbital ectopic glial tissue. The case is described herein of a 3-month-old baby presenting with an orbital glial hamartoma inseparable from the medial rectus muscle. The diagnosis was based on the histopathological features and a positive GFAP stain. The features of this case and the previously reported cases are discussed.

Advancement of Whitnall's ligament via the conjunctival approach for correction of congenital ptosis.

PURPOSE: To conduct a preliminary study on ptotic eyelids with unilateral, congenital, simple partial ptosis, operated by advancement of Whitnall's ligament via the conjunctival route. METHOD: A prospective, interventional, clinical study. RESULTS: A total of 10 patients were recruited. The ptosis was 4 mm or less (range 2-4 mm; mean 2.7) and LPS action was greater than 5 mm (range 6-14 mm; mean 9.7). The ptosis was corrected by advancement of Whitnall's ligament by plication of the levator aponeurosis via the conjunctival route. Postoperatively, correction within 1 mm of the normal lid height was taken as good correction. All patients were assessed for a minimum of one year with regard to the amount of correction, residual ptosis, lid lag and lagophthalmos. In our study, good correction, i.e. within 1 mm of the normal fellow eye in primary gaze, was obtained in 80% of patients. Patients with more than or equal to 8 mm levator function gave better results. Undercorrection occurred in two patients. Lid lag and lagophthalmos occurred in all patients but was within acceptable limits. CONCLUSION: Advancement of Whitnall's ligament by plication of the levator aponeurosis via the conjunctival route is a viable procedure, which has all the advantages of performing the same technique via the cutaneous approach, i.e. shorter surgical time, minimal dissection of tissue planes and reversibility. The conjunctival approach has the added advantage of being cosmetically more acceptable as there is no visible scar on the lid. The technique also offers satisfactory functional results with few (correctable) complications.

Pleomorphic adenomas of the lacrimal gland: a clinicopathological analysis.

PURPOSE: To analyse retrospectively 32 cases of pleomorphic adenoma of the lacrimal gland diagnosed over a 10-year period in a tertiary referral eye centre from North India. METHODS: The clinical features of 32 cases of pleomorphic adenomas diagnosed between 1991 and 2000 were analysed and the histopathological features reviewed light microscopically. RESULTS: Among the clinical features, a marked male predominance with younger age of presentation and left-sided dominance was noted. The duration of symptoms was less than 10 months in 28% cases. Histopathologically, the features included presence of cystic degeneration (15.6%) and squamous metaplasia (18.7%). Calcification, osteoid formation and malignant transformation (3.1% each) were occasionally observed. CONCLUSIONS: Pleomorphic adenomas of the lacrimal gland may present with duration of symptoms of less than 10 months. Cystic degeneration, squamous metaplasia, calcification or ossification may be observed in lacrimal gland pleomorphic adenomas, as has been described in pleomorphic adenomas of salivary glands. However, the presence of calcification and bone erosion radiologically in a lacrimal gland tumour does not necessarily indicate malignancy.

Dentigerous cyst in the maxillary sinus: a rare cause of nasolacrimal obstruction.

The main types of maxillary cysts are antral mucoceles, retention cysts, pseudocysts, dentigerous cysts and keratocysts. Despite the theoretical possibility of maxillary sinus cysts leading to nasolacrimal duct obstruction, only two cases have been reported in the literature so far. The present authors report this rare presentation of a dentigerous cyst with a tooth in the roof of the maxillary sinus, which led to nasolacrimal duct obstruction.