An intronic splice-site variant in MBTPS2 underlies ichthyosis follicularis with atrichia and photophobia syndrome.

Ichthyosis follicularis with atrichia and photophobia (IFAP) syndrome is a rare genodermatosis characterized by a classic triad of follicular ichthyosis, alopecia, and photophobia. We report a Chinese patient displaying features of IFAP triad along with painful palmoplantar keratoderma, recurrent infections, periorificial keratotic plaques, nail dystrophy, and pachyonychia. Whole-exome sequencing revealed an intronic variant (NM_015884.3: exon7:c.970+5G>A) in the gene MBTPS2. Sanger sequencing confirmed that the variant segerated with phenotype in the family. Sequencing of cDNAs derived from the patient indicated the variant introduced a new splice donor site, leading to partial skipping of exon 7 (r.951_970del). An in vitro mini-gene assay also revealed abnormal splicing of exon 7. This study presents a case complicated with X-linked IFAP syndrome and Olmsted syndrome, and highlights the significance of using validation assays to identify the pathogenicity of intronic variants in MBTPS2.

PACAP Induces Light Aversion in Mice by an Inheritable Mechanism Independent of CGRP.

The neuropeptides CGRP (calcitonin gene-related peptide) and PACAP (pituitary adenylate cyclase-activating polypeptide) have emerged as mediators of migraine, yet the potential overlap of their mechanisms remains unknown. Infusion of PACAP, like CGRP, can cause migraine in people, and both peptides share similar vasodilatory and nociceptive functions. In this study, we have used light aversion in mice as a surrogate for migraine-like photophobia to compare CGRP and PACAP and ask whether CGRP or PACAP actions were dependent on each other. Similar to CGRP, PACAP induced light aversion in outbred CD-1 mice. The light aversion was accompanied by increased resting in the dark, but not anxiety in a light-independent open field assay. Unexpectedly, about one-third of the CD-1 mice did not respond to PACAP, which was not seen with CGRP. The responder and nonresponder phenotypes were stable, inheritable, and not sex linked, although there was a trend for greater responses among male mice. RNA-sequencing analysis of trigeminal ganglia yielded hierarchical clustering of responder and nonresponder mice and revealed a number of candidate genes, including greater expression of the Trpc5 and Kcnk12 ion channels and glycoprotein hormones and receptors in a subset of male responder mice. Importantly, an anti-PACAP monoclonal antibody could block PACAP-induced light aversion but not CGRP-induced light aversion. Conversely, an anti-CGRP antibody could not block PACAP-induced light aversion. Thus, we propose that CGRP and PACAP act by independent convergent pathways that cause a migraine-like symptom in mice.SIGNIFICANCE STATEMENT The relationship between the neuropeptides CGRP (calcitonin gene-related peptide) and PACAP (pituitary adenylate cyclase-activating polypeptide) in migraine is relevant given that both peptides can induce migraine in people, yet to date only drugs that target CGRP are available. Using an outbred strain of mice, we were able to show that most, but not all, mice respond to PACAP in a preclinical photophobia assay. Our finding that CGRP and PACAP monoclonal antibodies do not cross-inhibit the other peptide indicates that CGRP and PACAP actions are independent and suggests that PACAP-targeted drugs may be effective in patients who do not respond to CGRP-based therapeutics.

Ichthyosis follicularis, atrichia and photophobia (IFAP) and hereditary mucoepithelial dysplasia: Two syndromes that share a common clinical spectrum.

Ichthyosis follicularis, atrichia and photophobia syndrome (IFAP) is an X-linked inherited disease caused by pathogenic variants in the gene encoding the membrane-bound transcription factor peptidase, site 2 (MBTPS2). Clinical presentation includes ichthyosis follicularis, alopecia, photophobia and developmental delay. Hereditary mucoepithelial dysplasia (HMD) is a dominantly inherited disease characterized by keratitis, non-scarring alopecia, skin lesions including follicular keratosis, perineal erythema, and mucosal involvement. Recently, variants in SREBF1, a gene coding for a transcription factor related to cholesterol and fatty acid synthesis, have been associated with the disease. These two syndromes share a common clinical spectrum. Here, we describe an IFAP syndrome patient with a novel variant in the MBTPS2 gene and an HMD patient with a previously reported variant in the SREBF1 gene. In addition, we present a review of the literature describing the triad characterized by non-scarring alopecia, keratosis follicularis, and ocular symptoms common in both IFAP and HMD patients to raise awareness of these underdiagnosed diseases. We also highlight the subtle differences in clinical presentation between the two disorders to better enable differentiation.

Limbal Stem Cell Dysfunction in Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome.

PURPOSE: To describe the presentation and management of limbal stem cell dysfunction in ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome. METHODS: A retrospective case report. RESULTS: A 6-day-old male infant was diagnosed with IFAP syndrome based on family history and a mutation detected in the MBTPS2 gene. Initial examination showed hyperkeratotic eyelids, madarosis, and lagophthalmos, but otherwise clear corneas. He developed bilateral central corneal epithelial defects spontaneously 6 months later, which were managed with aggressive lubrication, prophylactic antibiotics, and bilateral permanent lateral tarsorrhaphies at 7 months of age. During the procedure, the patient was noted to have bilateral limbal thickening, peripheral corneal pannus with underlying stromal scarring, and late fluorescein staining of the corneal surface. Anterior segment optical coherence tomography demonstrated a significantly abnormal and hyperreflective epithelial surface overlying a thinned corneal stroma, suggestive of limbal stem cell dysfunction. The corneal surface was maintained with lubrication and tarsorrhaphy and has remained stable since. CONCLUSIONS: The progressive conjunctivalization, spontaneous epithelial defects, and anterior segment optical coherence tomography features are highly suggestive of limbal stem cell dysfunction in IFAP syndrome. Optimizing the ocular surface is of importance in the management of children with this rare disease.

Characterization of Chlamydomonas Very High Light-tolerant Mutants for Enhanced Lipid Production.

Biodiesel production from microalgae is still not commercially realized due to the high cost of production. High light-tolerance has been suggested as a desirable phenotype for efficient cultivation in large scale production systems under fluctuating outdoor conditions. Nevertheless, it has not been shown if algae with such a phenotype would have better efficiency for lipid production. To determine lipid productivity in high light-tolerant mutants, and to understand the pathways involved in high light-tolerant phenotype, two very high light-tolerant mutants of the green alga Chlamydomonas reinhardtii - CAL028_01_28 and CAL034_01_48 - were selected from eighteen high light-tolerant mutants from the CAL collection. Under high light intensity conditions, and the presence of reactive oxygen species, which are conditions constantly experienced by algae growing in open-pond environments, these strains exhibited higher photosynthetic efficiency and improved survival. The physiological characterization of these mutants revealed that the detoxification of ROS by carotenoids and antioxidant enzymes is crucial for their growth under high light conditions. Neither mutant was affected in terms of its ability to accumulate lipid under nitrogen-depleted condition. More importantly, lipid productivity under high light conditions increased twofold in these mutants compared to that of the wild-type. Taken together, very high light-tolerant mutants confer a high potential for biofuel production under outdoor conditions, and their improved ability to survive under oxidative stress is an important key for efficient growth under outdoor conditions.

Genetics of Inherited Ichthyoses and Related Diseases.

Inherited ichthyoses are classified as Mendelian disorders of cornification (MEDOC), which are defined on the basis of clinical and genetic features and are mainly divided into non-syndromic and syndromic ichthyoses. Numerous genes, which encode for corresponding proteins, are involved in the normal differentiation of keratinocytes (cornification) and participate in the formation of a functional epidermal barrier. To date, mutations in more than 50 genes are known to result in various types of ichthyoses. Thanks to modern genetic diagnostic methods based on targeted next generation sequencing (NGS), approximately 80-90% of cases can be resolved at present. Further sequencing methods covering the whole exome (WES) or whole genome (WGS) will obviously elucidate another portion of the remaining unknown ichthyoses in the future.

Recessive Mutations in AP1B1 Cause Ichthyosis, Deafness, and Photophobia.

We describe unrelated individuals with ichthyosis, failure to thrive, thrombocytopenia, photophobia, and progressive hearing loss. Each have bi-allelic mutations in AP1B1, the gene encoding the ß subunit of heterotetrameric adaptor protein 1 (AP-1) complexes, which mediate endomembrane polarization, sorting, and transport. In affected keratinocytes the AP-1 ß subunit is lost, and the γ subunit is greatly reduced, demonstrating destabilization of the AP-1 complex. Affected cells and tissue contain an abundance of abnormal vesicles and show hyperproliferation, abnormal epidermal differentiation, and derangement of intercellular junction proteins. Transduction of affected cells with wild-type AP1B1 rescues the vesicular phenotype, conclusively establishing that loss of AP1B1 function causes this disorder.

Mutations in ARL2BP, a protein required for ciliary microtubule structure, cause syndromic male infertility in humans and mice.

Cilia are evolutionarily conserved hair-like structures with a wide spectrum of key biological roles, and their dysfunction has been linked to a growing class of genetic disorders, known collectively as ciliopathies. Many strides have been made towards deciphering the molecular causes for these diseases, which have in turn expanded the understanding of cilia and their functional roles. One recently-identified ciliary gene is ARL2BP, encoding the ADP-Ribosylation Factor Like 2 Binding Protein. In this study, we have identified multiple ciliopathy phenotypes associated with mutations in ARL2BP in human patients and in a mouse knockout model. Our research demonstrates that spermiogenesis is impaired, resulting in abnormally shaped heads, shortened and mis-assembled sperm tails, as well as in loss of axonemal doublets. Additional phenotypes in the mouse included enlarged ventricles of the brain and situs inversus. Mouse embryonic fibroblasts derived from knockout animals revealed delayed depolymerization of primary cilia. Our results suggest that ARL2BP is required for the structural maintenance of cilia as well as of the sperm flagellum, and that its deficiency leads to syndromic ciliopathy.

A novel mutation in MBTPS2 causes ichthyosis follicularis, alopecia, and photophobia syndrome.

BACKGROUND: The ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome is a rare X-linked genodermatosis characterized by noninflammatory spiny follicular hyperkeratosis, severe photophobia, and non-scarring alopecia with variable severities. IFAP syndrome results from mutations in the gene encoding the membrane-bound transcription factor peptidase, site 2 (MBTPS2). METHODS: We present an 11-year-old male with typical clinical features of IFAP syndrome, including diffuse follicular hyperkeratosis, alopecia, photophobia, psoriasiform plaques, short statue, nail dystrophy, mental retardation, and seizures. RESULTS: A novel missense mutation (NM_015884.4: c.1298T > C; NP_056968.1: p. L433P) in the membrane-bound transcription factor peptidase, site 2 gene (MBTPS2) was identified in our patient. The heterozygous MBTPS2 mutation was identified in his mother but not his father. CONCLUSION: This study demonstrated a novel MBTPS2 mutation in a patient with IFAP syndrome and thus expands the known MBPTS2 molecular repertoire.

Retinal phenotypic characterization of patients with ABCA4 retinopathydue to the homozygous p.Ala1773Val mutation.

Purpose: To describe the retinal clinical features of a group of Mexican patients with Stargardt disease carrying the uncommon p.Ala1773Val founder mutation in ABCA4. Methods: Ten patients carrying the p.Ala1773Val mutation, nine of them homozygously, were included. Visual function studies included best-corrected visual acuity, electroretinography, Goldmann kinetic visual fields, and full-field electroretinography (ERG). In addition, imaging studies, such as optical coherence tomography (OCT), short-wave autofluorescence imaging, and quantitative analyses of hypofluorescence, were performed in each patient. Results: Best-corrected visual acuities ranged from 20/200 to 4/200. The median age of the patients at diagnosis was 23.3 years. The majority of the patients had photophobia and nyctalopia, and were classified as Fishman stage 4 (widespread choriocapillaris atrophy, resorption of flecks, and greatly reduced ERG amplitudes). An atypical retinal pigmentation pattern was observed in the patients, and the majority showed cone-rod dystrophy on full-field ERG. In vivo retinal microstructure assessment with OCT demonstrated central retinal thinning, variable loss of photoreceptors, and three different patterns of structural retinal degeneration. Two dissimilar patterns of abnormal autofluorescence were observed. No apparent age-related differences in the pattern of retinal degeneration were observed. Conclusions: The results indicate that this particular mutation in ABCA4 is associated with a severe retinal phenotype and thus, could be classified as null. Careful phenotyping of patients carrying specific mutations in ABCA4 is essential to enhance our understanding of disease expression linked to particular mutations and the resulting genotype-phenotype correlations.

Clinical, biochemical, and genetic aspects of Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS) is caused by an autosomal recessive mutation in ALDH3A2, which encodes the fatty aldehyde dehydrogenase responsible for the metabolism of long-chain aliphatic aldehydes and alcohols. The pathophysiologic accumulation of aldehydes in various organs, including the skin, brain, and eyes, leads to characteristic features of ichthyosis, intellectual disability, spastic di-/quadriplegia, and low visual acuity with photophobia. The severity of the clinical manifestations thereof can vary greatly, although most patients are bound to a wheelchair due to contractures. To date, correlations between genotype and phenotype have proven difficult to document due to low disease incidence and high heterogenetic variability in mutations. This review summarizes the clinical characteristics of SLS that have been found to contribute to the prognosis thereof, as well as recent updates from genetic and brain imaging studies. In addition, the differential diagnoses of SLS are briefly illustrated, covering cerebral palsy and other genetic or neurocutaneous syndromes mimicking the syndrome.

Diurnal preference, mood and the response to morning light in relation to polymorphisms in the human clock gene PER3.

PER3 gene polymorphisms have been associated with differences in human sleep-wake phenotypes, and sensitivity to light. The aims of this study were to assess: i) the frequency of allelic variants at two PER3 polymorphic sites (rs57875989 length polymorphism: PER3 4, PER3 5; rs228697 SNP: PER3 C, PER3 G) in relation to sleep-wake timing; ii) the effect of morning light on behavioural/circadian variables in PER3 4 /PER3 4 and PER3 5 /PER3 5 homozygotes. 786 Caucasian subjects living in Northern Italy donated buccal DNA and completed diurnal preference, sleep quality/timing and sleepiness/mood questionnaires. 19 PER3 4 /PER3 4 and 11 PER3 5 /PER3 5 homozygotes underwent morning light administration, whilst monitoring sleep-wake patterns and the urinary 6-sulphatoxymelatonin (aMT6s) rhythm. No significant relationship was observed between the length polymorphism and diurnal preference. By contrast, a significant association was observed between the PER3 G variant and morningness (OR = 2.10), and between the PER3 G-PER3 4 haplotype and morningness (OR = 2.19), for which a mechanistic hypothesis is suggested. No significant differences were observed in sleep timing/aMT6s rhythms between PER3 5 /PER3 5 and PER3 4 /PER3 4 subjects at baseline. After light administration, PER3 4 /PER3 4 subjects advanced their aMT6s acrophase (p < 0.05), and showed a trend of advanced sleep-wake timing. In conclusion, significant associations were observed between PER3 polymorphic variants/their combinations and both diurnal preference and the response to light.

Understanding the phenotypic similarities between IFAP and Olmsted syndrome from a molecular perspective: the interaction of MBTPS2 and TRPV3.

Ichthyosis Follicularis, Atrichia, and Photophobia (IFAP) is a severe rare genetic disorder caused by mutations in the gene encoding the Membrane-Bound Transcription Factor Peptidase, Site 2 (MBTPS2). Olmsted syndrome is another rare genetic disease with overlapping clinical features caused by mutations in the gene encoding the Transient Receptor Potential Cation Channel, subfamily V (TRPV3). Mutations in MBTPS2 have been recently reported in Olmsted syndrome, underscoring the overlap and the confusion in separating Olmsted from IFAP syndrome. We studied a Lebanese family with IFAP syndrome both, clinically and molecularly, and investigated whether there is a cross relation between TRPV3 and MBTPS2. We identified a recurrent mutation designated p.F475S in MBTPS2 in the affected individuals. This mutation was not found in 100 control individuals from the same population. We determined that TRPV3 regulatory region is a target for MBTPS2. In addition, there was an increased cell death in the cells transfected with the mutant versus the wild-type MBTPS2. In conclusion, we identified a direct regulatory effect of MBTPS2 on TRPV3 which can partially contribute to the overlapping clinical features of IFAP and Olmsted syndromes under a common signaling pathway.

Ichthyosis follicularis with alopecia and photophobia syndrome (IFAP): A Case Report.

IFAP syndrome is a rare autosomal recessive X-linked disease characterized by the triad of alopecia universalis, severe photophobia, and follicular ichthyosis. It is caused by loss of function of the gene MBTPS2. Its severity varies and there are only a few reports in the literature. We present a patient with characteristic clinical features and a mutation not previously reported.

Fine-tuning light sensitivity in the starry flounder (Platichthys stellatus) retina: Regional variation in photoreceptor cell morphology and opsin gene expression.

Vertebrate color vision relies on the differential expression of visual pigment proteins (opsins) in cone photoreceptors of the retina. The diversity of opsins and their retinal expression patterns appear greatest for animals that experience variable light habitats, as is the case with flatfishes. Yet, opsin repertoires and expression patterns in this group of fishes are poorly described. Here, we unveil the visual opsin expression patterns of juvenile starry flounder (Platichthys stellatus) and describe the localization of cone types, their visual pigments and opsin expression. Juvenile starry flounder express eight opsins (Rh1, Sws1, Sws2A1, Sws2A2, Sws2B, Rh2A1, Rh2A2, Lws) and possess a corresponding number of photoreceptor visual pigments, with peak absorbance ranging from 369 to 557 nm. Retinal (vitamin A1) was the only chromophore detected in the retina. Intraretinal variation in opsin abundance consisted of greater expression of both RH2, and lesser expression of SWS1 and both SWS2A, opsin transcripts in the dorsal compared to the ventral retina. Overall cone density was greater in the dorsal retina which was also characterized by a larger proportion of unequal double cones compared with the ventral retina. Together, our results suggest that large opsin repertoires serve to optimize visual function under variable light environments by differential expression of opsin subsets with retinal location.

Variant lattice corneal dystrophy associated with compound heterozygous mutations in the TGFBI gene.

BACKGROUND/AIMS: To report the clinical, histopathological and genetic features of a variant of lattice corneal dystrophy (LCD) associated with two pathogenic mutations in the transforming growth factor-B-induced (TGFBI) gene. METHODS: Clinical characterisation was performed by slit lamp examination and in vivo confocal microscopic imaging (IVCM). Histopathological characterisation was performed with light microscopic examination of an excised corneal button and a peripheral blood samples were collected for TGFBI screening. RESULTS: A 42-year-old woman presented with progressive photophobia and decreased visual acuity in both eyes. Slit lamp examination demonstrated punctate and linear branching opacities in the mid and posterior corneal stroma, corresponding to hyper-reflective opacities noted on IVCM and amyloid deposition noted on histopathological examination of an excised corneal button. TGFBI screening revealed two previously reported heterozygous missense mutations: c.337G>A (p.(Val113Ile)) in exon 4 and c.1673T>C (p.(Leu558Pro)) in exon 12. Screening of an affected sibling with a similar phenotype revealed that she was also heterozygous for both mutations, while screening of another sibling with punctate but not linear stromal opacities revealed that she was heterozygous for only the p.(Leu558Pro) mutation. CONCLUSIONS: The p.(Val113Ile) mutation results in an alteration of the atypical LCD phenotype associated with the p.(Leu558Pro) mutation. This represents only the second report of the alteration of the phenotype of a TGFBI dystrophy by a second, non-homozygous pathogenic mutation, and thus provides insight into the phenotype-genotype correlation of the TGFBI dystrophies.

A novel mutation and variable phenotypic expression in a large consanguineous pedigree with Jalili syndrome.

PurposeJalili syndrome is an autosomal recessive disorder characterized by simultaneous appearance of cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI). Mutations in CNNM4 gene have been identified as the underlying cause of the syndrome. In this study, we investigated a large affected family to identify the causative mutation.Patients and MethodsA seven-generation family with 24 members affected with Jalili syndrome were enrolled in the study. Comprehensive ophthalmologic and dental examinations were performed on them. The entire coding region of CNNM4 gene was sequenced for detection of potential mutations.ResultsOcular examinations showed nystagmus and photophobia along with early onset visual impairment. Fundoscopic exams revealed a spectrum of macular dystrophies in different family members, from macular coloboma and advanced form of beaten bronze macular dystrophy (bull's eye) to milder form of macular thinning along with a range of pigmentary changes and vascular attenuation in the posterior pole and periphery. Scotopic and photopic electro-retinographic responses (ERGs) were extinguished or significantly depressed. Mutation analysis revealed a novel mutation (c.1091delG) in homozygous form in the patients and as a heterozygous form in the normal carrier subjects.ConclusionWe identified a novel homozygous deleterious mutation in CNNM4 gene which causes Jalili syndrome.