Tyrp1 mutation drives color variation via melanin reduction and collagen deposition in Chinese soft-shelled turtles (Pelodiscus sinensis).

Usher syndrome (USH) is an inherited disorder that causes bilateral sensorineural hearing loss (SNHL), retinitis pigmentosa, and vestibular defects. It represents the most common cause of combined deaf-blindness worldwide. Mutations in the nine known underlying genes are categorized into three types: USH type 1 has the earliest, most severe onset, while the much more common USH type 2 is comparatively mild with delayed onset and moderate symptoms. USH type 3 is very rare and exhibits variable clinical manifestations. The current standard of care for SNHL in USH is comprised of conventional hearing aids and/or cochlear implantation depending on the severity of symptoms. However, existing studies on treatment outcomes generally have rather short follow-up durations from a single institution and rarely distinguish between the individual USH subtypes. This retrospective multicenter cohort study analyzed 655 audiograms of 33 patients (66 ears) with genetically confirmed USH. Patient-specific characteristics and treatments were correlated with pure-tone average thresholds and speech perception performance over a mean (SD) of 7 yrs and 10 mo (9 yrs and 11 mo) overall and 8 yrs and 2 mo (6 yrs and 3 mo) after cochlear implantation. Conventional hearing aids improved thresholds on average (SD) by 20.1 (10.9) dB HL regardless of age, but aided hearing still deteriorated concurrently with the natural progression of SNHL. In patients with severe-to-profound SNHL or complete deafness, cochlear implantation rescued hearing to average thresholds of 37.9 (7.0) dB HL 1 yr post-implantation, 37.3 (10.3) dB HL after 2 years, and 27.5 (7.1) dB HL after 15 to 20 yrs. Every single patient who received an implant benefited from it, irrespective of the age at implantation or the causative USH mutation. With new gene therapies for USH in development, the findings reported here can serve as a benchmark for the comparison of novel treatments with the current clinical standard of care around the world. Larger-scale studies with more consistent monitoring of hearing and speech perception ability, as well as more extensive genetic testing, could further elucidate the benefits of current treatments for different (sub-)types of USH.

Phaeochromocytomas (PCCs) and paragangliomas (PGLs), are rare neuroendocrine tumours that arise in the neural crest (NC)-derived adrenal medulla and the paraganglia, respectively. Approximately 10%-15% of patients with PCCs and 35%-40% with PGLs go on to develop metastatic disease, leading to a reported median overall survival of 7 years. The development of prognostic markers and subsequent personal therapeutic strategies are hindered by a lack of understanding of tumourigenesis. In other organs, cells with stem-like properties are at the root of tumour initiation and maintenance, due to their ability to self-renew and give rise to differentiated cells. We have recently shown that, in the human adrenal, a subset of sustentacular cells, endowed with a support role, are in fact SOX2+ postnatal adrenomedullary stem cells, that are specified along the neural crest migratory route. In this study, we intended to determine if SOX2+ cells in PCCs and PGLs can behave as tumour-initiating stem cells. Using expression and transcriptomic studies, we demonstrate the presence of SOX2/SOX2-expressing cells across a broad range of PCCs and PGLs, irrespective of tumour aggressiveness, location, and causative mutation. In silico analyses reveal the co-expression of SOX2 and chromaffin cell markers in the tumour, and the active proliferation of these double-positive cells. Isolation of these cells in vitro in stem cell-promoting media, and their xenotransplantation on chicken chorioallantoic membranes, demonstrates that they have the potential to expand and metastasise in ovo, supporting their potential as tumour-initiating cells.

Sake yeast Kyokai no. 11 (K11) is an ethanol-tolerant mutant of Kyokai no. 7 (K7) and produces a higher ethanol concentration in the sake mash than K7. A previous study revealed that stress-induced genes under the control of STRE elements were upregulated in K11. To elucidate the causal mutation responsible for ethanol tolerance, we compared the genome sequences of the ethanol-tolerant mutants (K11 and K7AT2, a newly isolated ethanol-tolerant mutant of K7) with that of their parental strain, K7. We identified a shared loss of heterozygosity region in the left arm of chromosome X in both mutants. We focused on CYR1 in this region, as it encodes adenylate cyclase, which negatively regulates expression of STRE-regulated genes through the upregulation of protein kinase A. Nucleotide 2066 of CYR1 was changed from G/A (amino acids Arg/His) in K7 to A/A (amino acids His/His) in K11 and K7AT2. When the plasmid containing CYR12066G was introduced into K11 or K7AT2, the stress tolerance of the transformants decreased to the level of K7, whereas the introduction of CYR12066A had a minimal effect. Consistently, disruption of the CYR12066G allele in K7 increased stress tolerance, whereas disruption of CYR12066A decreased stress tolerance. Furthermore, when CYR1 in a laboratory haploid strain was disrupted and either the CYR12042A or CYR12042G allele of S288C (corresponding to K7CYR12066) was introduced into the disruptant, the transformants with CYR12042A showed higher stress tolerance than those with CYR12042G. We concluded that the CYR1G2066A mutation was responsible for ethanol tolerance in K11.

Huntington's disease (HD) is an incurable, neurodegenerative disorder. While the causative mutation - CAG expansions within the coding region of the Huntingtin (HTT) gene - has been identified over 30 years ago, the pathological mechanisms underlying HD are still not clear. The abnormal CAG track encodes a polyglutamine (polyQ) expanded protein, which leads to HTT protein misfolding. These polyQ aggregates can form insoluble inclusion bodies (IBs); however, whether IBs are protective or detrimental remains debatable. Here we developed fluorescent iPSC-based human neuronal models for polyQ-related disorders. Comparing cell death in IB+ and IB- iPSC-derived neurons, growing side-by-side, we demonstrate that polyQ IBs have a significant protective effect. Remarkably, knocking out ATF3 prevented polyQ-IB formation and rendered the cells more vulnerable to induced stress. Taken together, our results reveal ATF3's role in polyQ IB formation in human NPCs, and demonstrate that polyQ IBs protect cells from stress-induced death.

Tobacco (Nicotiana tabacum) is one of the most important commercial crops. It is an allotetraploid with two subgenomes derived from two wild diploid species: the maternal ancestor Nicotiana sylvestris and the paternal ancestor Nicotiana tomentosiformis. The functional duplication of homologous genes derived from both subgenomes often hinders phenotypic screening because a recessive mutation on one homeolog is complemented by the other. In this study, to establish a forward genetics platform for the genus Nicotiana, we constructed an ethyl methanesulfonate-induced N. sylvestris mutant library with high mutation frequency and generated an improved-quality reference genome of this species. We phenotypically screened the mutants with reduced nicotine content and selected two non-allelic mutants from the library. MutMap analysis using the reference genome, and subsequent molecular analyses, identified causal mutations in aspartate oxidase 2 (AO2) and ethylene responsible factor 199 genes. We genotypically screened N. tabacum mutants for AO2 and confirmed that nicotine biosynthesis was significantly affected in N. tabacum mutants with nonsense mutations in AO2s in both subgenomes, as observed in N. sylvestris. Thus, screening the N.sylvestris mutant library and gene identification using the reference genome are promising forward genetic approaches for gene discovery. This would allow researchers to improve N. tabacum by using reverse genetics and to elucidate the molecular mechanisms underlying traits. This study opens new avenues in Nicotiana functional genomics.

Carotenoids play fundamental roles in avian ecology and evolution. Full expression of carotenoid-based plumage relies on key molecular mechanisms that regulate the uptake, processing and deposition of dietary pigments into target tissues. The blue Gouldian finch (Erythrura gouldiae) variety is explained by an autosomal recessive locus that affects carotenoid coloration. Using whole-genome sequencing data and genetic mapping, we identified a splice-acceptor mutation in scavenger receptor B1 (SCARB1) that abolishes carotenoid-based pigmentation. Biochemical analyses revealed that blue individuals circulate extremely low concentrations of dietary carotenoids, confirming a genetic disruption of carotenoid uptake and transport in the gut. Through genotyping of the candidate causative mutation in carotenoid-containing and carotenoid-free mask feathers of a mosaic blue individual, we further demonstrate that somatic reversion of blue rescues SCARB1 function and locally restores carotenoid deposition in feathers. Finally, by comparing the transcriptomes of carotenoid-containing and carotenoid-free feather follicles from different plumage regions of wild-type birds, we show that SCARB1 expression alone is not sufficient to trigger carotenoid pigmentation. These findings reinforce the role of SCARB1 as a key facilitator of carotenoid uptake and transport in the gut, while also establishing its necessity for localized uptake of carotenoids to developing feather follicles.

Abstract Background The expansion of the causative mutations to the rigid thin filament changed the description of hypertrophic cardiomyopathy (HCM) from an illness of the cardiac motor to a syndrome of the cardiac sarcomere and significantly extended the gasp of the potential molecular pathogenic mechanism. An interesting hypothesis concerning disease mechanism posted that the diverse medical prognoses in the familial type of HCM may possibly be related to mutations in self-regulating protein machinery of the sarcomere. The current studies conducted by some researchers elaborated on the various genetic alterations inside the genes encoding for the sarcomere cardiac proteins, alpha tropomyosin, troponin T, and myosin protein components. The regularity of gene alteration in the alpha tropomyosin protein (TPM1) is lesser, contributing to 5% of FHC. Currently, the D175N gene mutation has been recognized in various unrelated populations, signifying that this spot could be an abnormal gene “hot spot” for the disease. Purpose The aims and objectives of this project research is to produce a wild type of normal protein and mutant genetic proteins (E180G and D175N) which are clinically involved in familial hyper cardiomyopathy (FHCM). Bearing in mind that the main effect of mutations E180G and D175N are mainly related to the thermal stability of the protein; this research also investigated the differences between the thermal stability of wild type and mutated protein types using a Dye base fluorescent method of analysis. Methods (1)Preparation and Storage of Competent XL-1, BL2 and Escherichia Coli Cells applicable to transformation and transfection (2) Tropomyosin Preparation (3) DNA Purification (4) Column Chromatography analysis of tropomyosin (Wild Type Protein) (5) Preparation of mutated Protein (D175N and E180G) (Site Directed Mutagenesis) (6) Column Chromatography analysis of mutated Proteins (7) Measurement of the thermal Stability of Wild Type (Lysozyme) and mutated proteins (D175N and E180G) Using the Dye Base Fluorescent method (8) Media culture of XL1 cells and BL2 on agar media (9) DNA and protein gel electrophoresis (10) Resuspension of protein pellet with Potassium Phosphate. Results A wild type of normal protein and mutant genetic proteins (E180G and D175N) which are clinically involved in familial hyper cardiomyopathy (FHCM) were produced. The DNA and protein gel electrophoresis was conducted and the presence of the protein on the protein bands was noted, which indicates a high synthesis and purification process. The absorbance of tropomyosin normal protein using spectrophotometer measurements was performed and the molecular weight of the protein was found to be 32797 Da. At 280 nm wavelength, the absorbance of the protein was 0.129, and the protein concentration was found to be 11.64mg/ml. The absorbance of D175N protein using spectrophotometer measurements was conducted and the molecular weight of the protein was found to be 32797 Da. At 280 nm wavelength, the absorbance of the protein was 0.032, and the protein concentration was found to be 5.25mg/ml. The absorbance of E180G protein using spectrophotometer measurements was conducted and the molecular weight of the protein was found to be 32797 Da. At 280 nm wavelength, the absorbance of the protein was 0.031, and the protein concentration was found to be 5.43mg/ml. Thermal denaturation studies of normal tropomyosin and mutant tropomyosin (E180G and D175N) show a cooperative interaction between folding of the N-domain and C-regions of tropomyosin. HCM mutations E180G and D175N prominently destabilized the tropomyosin N-domain, which indirectly affected cooperative interactions between N- and C-terminal regions of tropomyosin. Conclusion Recombinant human tropomyosin’s were produced which serves as a model protein to study the interactions that govern the stability of the thin filament. Two mutations (E180G and D175N) described as causing cardiomyopathy were introduced in the cDNA encoding the human skeletal muscle tropomyosin. Thermal denaturation studies of control and mutant tropomyosin (E180G and D175N) show a cooperative interaction between folding of the N-domain and C-regions of tropomyosin. HCM mutations E180G and D175N prominently destabilized the tropomyosin N-domain, which indirectly affected cooperative interactions between N- and C-terminal regions of tropomyosin. The experimental result on this current study suggested that HCM mutations locally destabilize tropomyosin, leading to an increased thin filament Calcium sensitivity, and the degree of disruption of the tropomyosin interaction by the FHC mutations may be directly correlated with the severity of the disease. For future prospect, future biochemical analysis of several other FHC mutations will be needed to establish a definite correlation between the enzymatic impairment between different mutants and their clinical phenotype of heart disease.

Background/Objectives: Heterotopic ossification (HO), the aberrant formation of bone within soft tissues, arises either from rare genetic mutations or more commonly from traumatic insults. It is a major cause of morbidity not only in individuals harboring causative mutations, but also in those undergoing musculoskeletal surgery or trauma and in soldiers sustaining blast or burn injuries. Bone morphogenetic protein (BMP) signaling is a central driver of both hereditary and acquired forms of HO. Primary cilia are nonmotile, antenna-like organelles that extend from the cell surface and serve as crucial sensory and signaling hubs by concentrating key pathway components within a confined volume at the ciliary tip. However, their functional role in the pathogenesis of traumatic HO remains poorly understood. Methods: We investigate the role of primary cilia in traumatic HO using a genetically modified mouse model and cellular model. Results: We demonstrate that BMP signaling is attenuated when primary cilia function is disrupted. Both ciliation frequency and ciliary length were reduced in Scleraxis-CreERT2; Intraflagellar transport 88floxed/floxed (Scx-CreERT2;Ift88fl/fl) tenocytes. Deletion of Ift88 effectively suppressed pathological BMP signaling and inhibited HO formation. Conclusions: These findings establish that functional primary cilia are required for traumatic HO development and highlight ciliary regulation as a potential therapeutic avenue for preventing or mitigating post-traumatic HO.

Hereditary ataxias are a heterogeneous group of neurodegenerative disorders characterized by impaired balance and coordination, often due to cerebellar dysfunction. Despite advances in identifying genetic causes, animal models remain essential for dissecting underlying mechanisms and testing therapeutic strategies. Here we describe a mouse model of spastic ataxia and myopathy caused by a missense mutation in Tuba4a (n.A626C, p.Gln176Pro). In an ENU mutagenesis screen, a male C57BL/6J mouse exhibiting muscle wasting and an intention tremor starting at approximately 4 weeks-of-age was identified. The male was bred by in vitro fertilization to BALB/cByJ oocyte donors. Genetic mapping determined dominant inheritance and localized the mutation to Chromosome 1. Genome sequencing revealed single nucleotide polymorphisms (SNPs) in serine threonine kinase 36 (Stk36Y1003N) and alpha-tubulin 4A (Tuba4aQ176P) in the mapping interval. These SNPs were CRISPR-engineered into C57BL/6J mice, which confirmed the Tuba4aQ176P variant as the causative mutation. Mutant mice are normal at 3 weeks, except for decrement in muscle response following repetitive nerve stimulation. However, by 30 days these mice have ataxia, Purkinje neuron degeneration, and extensive skeletal muscle defects, which contribute to a decreased lifespan. Dominant TUBA4A mutations in humans are associated with spastic ataxia type 11 (SPAX11), congenital myopathy type 26 (CMYO26), and frontotemporal dementia/amyotrophic lateral sclerosis type 9 (FTDALS9). Our mice exhibit hallmark features of SPAX11 and CMYO26, but do not show motor neuron degeneration. This specificity makes this model a valuable tool for studying cell-type selective effects of TUBA4A mutations in neurodegeneration and myopathy.

Genome-wide association studies (GWAS) have become a standard approach for identifying quantitative trait loci associated with diverse phenotypic traits. Further investigation of the locus - specifically, the search for the causal gene and mutation - may present various challenges. One of the challenges is genetic heterogeneity (or locus heterogeneity), when alleles from different closely located genes can influence the same trait. Recently, using GWAS, we found the qDTF-7 locus on soybean chromosome 3, which is associated with flowering time under Novosibirsk conditions. Initially, we identified GmTOE1, an ortholog of TOE1 (TARGET OF EAT1), a known flowering-time regulator in Arabidopsis, as the most likely candidate gene for this locus. Four major haplotypes were identified in GmTOE1, which are associated with soybean flowering and maturity and are likely to provide soybean adaptation to northern latitudes. However, this gene showed only a very weak association with soybean flowering in the Novosibirsk region compared to the Oryol region, suggesting the presence of another gene within the locus that influences flowering time. We therefore re-analyzed genes in the qDTF-7 locus and identified GmRVE8c, an Arabidopsis RVE8 (REVEILLE 8) ortholog, located ~21 kb upstream of GmTOE1; RVE8 is a circadian clock component involved in plant development. After studying the natural variation of the GmRVE8c genes, we found four major haplotypes that arose due to three nonsynonymous substitutions and one 19-bp deletion leading to a frameshift. To identify three haplotypes, GmRVE8chap1, 3, 4, which are predominant in improved soybean cultivars, we developed DNA markers. Using these markers, we genotyped 129 soybean accessions, the developmental time of which had been studied in the Novosibirsk and Oryol regions. Using our data and data from SoyOmics, we found the GmRVE8chap3 and GmRVE8chap4 haplotypes to be associated with late flowering and maturity in soybean. The early-maturing haplotype GmRVE8chap1 is predominant in cultivars from northern regions and is likely associated with the adaptation of soybean to high latitudes. The GmRVE8chap4 haplotype is in complete linkage with the early-maturing allele GmTOE1C, whereas the GmRVE8chap3 haplotype shows strong linkage with the late maturing allele GmTOE1T. Furthermore, the ANOVA results indicate an interaction between GmRVE8c and E1, the major regulator of flowering in soybean. This interaction is manifested as a stronger effect of the GmRVE8chap3,4 haplotypes on flowering and maturity in the genetic background of the e1-as allele compared with E1. Together, these findings define a complex and intriguing locus, which may serve as a possible example of a genetically heterogeneous locus.

Nephrotic syndrome (NS) is commonly managed with glucocorticoid (GC) therapy, yet about 10%-30% of children do not achieve remission after an adequate initial steroid course and are classified as steroid-resistant nephrotic syndrome (SRNS); in adults, proportions are generally higher and heterogeneous across histologies. Currently, genetic testing can identify causative mutations in 30% of SRNS cases, highlighting the need for complementary pre-treatment stratification approaches. This review synthesizes human evidence linking epigenetic dysregulation to GC responsiveness, highlighting differential DNA methylation patterns in genes such as NLRP3 and SOCS3. Simultaneously, the expression levels of microRNAs (miRNAs) such as miR-142 and miR-30 have been shown to be associated with the efficacy of GC treatment. We propose a multi-biomarker integrative analysis strategy that combines methylation profiles with miRNA expression and emerging histone modification signals for pre-treatment risk stratification and prediction of therapeutic response, thereby reducing ineffective steroid exposure and enabling mechanism-informed management pending prospective validation.

Pontocerebellar hypoplasia (PCH) comprises a group of rare neurodevelopmental disorders characterized by prenatal-onset cerebellar and pontine atrophy, often leading to severe motor and cognitive impairments. While advances in genetic diagnostics have improved our understanding, the full spectrum of causative mutations remains unclear, particularly in underrepresented populations. This study aims to delineate the clinical and genetic characteristics of Iranian patients with PCH. We conducted comprehensive clinical evaluations, brain imaging, and laboratory tests, followed by whole-exome sequencing (WES) in Iranian patients with PCH to establish genotype-phenotype correlations. In silico structural and modeling analyses were performed to assess the impact of novel variants on protein function. Ten unrelated patients were diagnosed with different PCH subtypes. Microcephaly and spasticity were observed in 80% of cases, while hypotonia, psychomotor retardation, and speech problems were present in all patients. Additional features included nystagmus (40%), ataxia (20%), decreased deep tendon reflexes (50%), respiratory insufficiency (10%), feeding difficulties (30%), scoliosis (10%), cognitive deficits (20%), seizures (40%), and vision problems (10%). Genetic analysis identified eight pathogenic variants, including four reported mutations in RARS2, EXOSC3, and TSEN54, and four novel mutations in SEPSECS, and RARS2. A recurrent missense variant (EXOSC3: c.395 A > C) was detected in 40% of cases. This study expands the mutational spectrum of PCH by identifying novel variants and underscores the disorder's genetic heterogeneity. The clinical manifestations ranged from mild developmental delay to severe neurodevelopmental decline with respiratory insufficiency and seizures. Our findings provide valuable insights into genotype-phenotype correlations, facilitating early diagnosis and personalized management strategies. Additionally, these results contribute to genetic counseling and future functional studies to elucidate disease mechanisms.

Pollen allergies are an increasingly serious public-health issue worldwide. Japanese cedar (Cryptomeria japonica D. Don, Cupressaceae) is an important forestry species in Japan that releases large amounts of airborne pollen in spring, causing severe allergic reactions. Planting male-sterile individuals is expected to reduce pollen dispersal effectively. ‘Fukushima-funen 3’ is a male-sterile individual whose causal gene has remained unidentified. Through test crossings, we determined that the gene responsible for male sterility in ‘Fukushima-funen 3’ is MS2, and that this individual is heterozygous at the MS1 locus. These findings were supported by microscopy observations of pollen development and genotyping using DNA markers targeting the causal mutations in MS1 and MS2 candidate genes. Sanger sequencing of the coding region of the MS2 candidate gene revealed that ‘Fukushima-funen 3’ has both a previously reported single-nucleotide substitution and a novel 8-bp deletion within the mutation site. We conducted marker-assisted selection on 1511 breeding materials collected from various regions of Japan using these two mutations as DNA markers, and identified eight breeding materials with male sterility alleles. Some of these individuals had male sterility alleles at multiple loci, implying their potential utility in gene-pyramiding-based breeding strategies. These findings will contribute to the genetic elucidation of male sterility in C. japonica and the development of trees with superior traits.

Nutritropism is a directional root growth response to nutrient gradients, and rice (Oryza sativa L.) roots show nutritropism toward sources containing ammonium. Here, we report characterization of an EMS-mutagenized rice plant that shows a complete defect in nutritropism. Genetic analysis of the mutant identified a nucleotide substitution as a candidate for the causal mutation; this mutation leads to an amino acid substitution (E111V) in an auxin influx carrier protein, OsAUX1 (LOC_Os01g63770, Os01g0856500). We generated novel allelic mutants using CRISPR/Cas9, and these independent mutant lines showed defects in nutritropism. We concluded that OsAUX1 is the gene required for nutritropism based on this result. Analysis of RFP fluorescence in root tips expressing the DR5::RFP reporter suggested an asymmetric distribution of auxin in nutritropic root bending, and the asymmetry was similar to that in gravitropism. Nutritropism of aux1 mutants was recovered by exogenous application of membrane-permeable 1-naphthaleneacetic acid (NAA) but not by impermeable 2,4-dichlorophenoxyacetic acid, indicating that passive diffusion of NAA into the cytosol from the medium is sufficient to imitate the OsAUX1 functions. Our results establish the involvement of auxin in nutritropism, indicating the similarity to gravitropism but not to hydrotropism. This provides insights into the mechanisms for integration of the complex tropic stimulations from environments.

While most individuals with familial medullary thyroid carcinoma (fMTC) carry RET mutations, in some instances the causative mutations remain unknown. We studied two related families with RET -negative fMTC in 21 affected individuals through linkage analysis, exome/genome sequencing, and high-density array comparative genomic hybridization. We identified a novel heterozygous 40kb intragenic SLC30A9 deletion which segregated with the disease in all affected individuals. The mutant transcript escaped nonsense-mediated decay and resulted in the production of N-terminally truncated proteins via translation reinitiation from in-frame AUG codons located downstream of the deletion. These proteins showed increased stability and their expression in an MTC cell line increased cell proliferation and clonogenic capacity, supporting an oncogenic role. These findings expand the genetic background of fMTC beyond RET mutations and implicate translation reinitiation in the etiology of cancer susceptibility syndromes secondary to structural genomic variants.

Variants in the keratin 6A (KRT6A) gene are a major cause of pachyonychia congenita (PC), a rare autosomal dominant disorder characterized by nail hypertrophy and other ectodermal abnormalities. This study aimed to identify the causative mutation in a PC family and investigate the underlying pathogenic mechanism. We performed exome sequencing on this PC pedigree and validated candidate variations using Sanger sequencing. In silico predictions and invitro experiments showed that the heterozygous missense variant c.512A>G in KRT6A was pathogenic, inducing protein aggregation and disrupting filamentous network structures. Enrichment analysis suggested that the PPAR signaling pathway played a crucial role in PC, with decreased expression of PPARβ/δ in HeLa cells. Comparative analysis of PC patients carrying the p.Asn171 variant revealed marked heterogeneity in clinical manifestations. Notably, oral leukokeratosis, a common phenotype in KRT6A mutation carriers, was not observed in the patients in this study. Interestingly, one patient presented with small papules around the lips and nasal bridge. We conclude that the c.512A>G variant in KRT6A is the genetic cause of this PC family, diagnosed as PC-K6a subtype. This study expands the phenotypic spectrum of congenital PC and suggests the PPAR signaling pathway as a potential therapeutic target.

Engineered cell therapies present an opportunity for endogenous, site-specific production of therapeutic agents. Here we describe a closed-loop cell therapy which secretes an inhibitor of Activin A, ActR2A-Fc, upon exposure to Activin A. We demonstrate in vivo therapeutic efficacy of this approach in a mouse model of fibrodysplasia ossificans progressiva (FOP), a morbid condition in which patients develop extensive heterotopic bony lesions in response to aberrant sensitivity to Activin A through a mutation in the type I BMP receptor ACVR1 (ACVR1 R206H). To blunt Activin A activity, we designed a transposon plasmid containing the transgene encoding ActR2A-Fc, with expression controlled by the BMP-responsive element (BRE). In cells containing the causative mutation, the BRE is pathologically activated upon exposure to Activin A. FOP-derived marrow cells modified with the BRE-ActR2AFc plasmid exhibited the desired closed-loop functionality, with increased ActR2A-Fc expression upon exposure to Activin A and reduced expression upon withdrawal of Activin A. Engineered marrow cells secreted bioactive ActR2A-Fc, and bone marrow transplantation of FOP marrow cells engineered with the BRE-ActR2AFc transposon into same-sex FOP mice resulted in absence of heterotopic bony lesions. Experiments with labeled, engineered FOP marrow cells verified trafficking of the therapeutic cells to sites at risk for FOP. These data provide proof-of-concept for the therapeutic utility of engineered cell therapy for the treatment of FOP.

Lesion-mimic mutants (LMMs) spontaneously develop necrotic lesions in the absence of pathogen infection or environmental stress, serving as ideal models for studying cell death, immune signaling, and the growth-defense balance in plants. In this study, we identified a rice LMM and mapped the causal mutation to the Uroporphyrinogen Decarboxylase 2 gene, which had not been previously functionally characterized within the tetrapyrrole biosynthesis (TBS) pathway. Knockdown of OsUROD2 resulted in lesion mimicry and down-regulated key TBS pathway genes, including OsCPOX, OsPPOX, OsChlH, OsChlD, OsChlI, and OsChlM. Further functional analyses revealed that OsCPOX knockdown or OsPPOX knockout both caused lesion formation and reduced chlorophyll content, whereas triple knockout of OsChlH/OsChlD/OsChlI or knockout of OsChlM resulted in chlorophyll deficiency. Subcellular localization assays showed that OsUROD2, along with OsCPOX, OsPPOX, OsChlH, OsChlD, OsChlI, and OsChlM, localizes to the chloroplast. Our results demonstrate that the chloroplast-localized TBS pathway is integral to viability, lesion mimicry and chlorophyll synthesis in rice, providing crucial insights into the molecular mechanisms linking tetrapyrrole metabolism to regulated cell death.

Aims: Understanding the epidemiology, pathophysiology, clinical manifestations, causative mutations and management of oculocutaneous albinism by reporting a case of a 17 year old affected by this disease. Study Design: Case report: 17-year-old male presenting oculocutaneous albinism who presented for an ophthalmology consultation due to a profound decrease in visual acuity, associated with nystagmus and photophobia that had been progressing since early childhood. Discussion and Literature Review: We will comprehensively examine all aspects of oculocutaneous albinism by reviewing the literature on its epidemiology, pathophysiology, clinical manifestations, differential diagnosis, treatment, and prognosis. Conclusion: Advances in molecular diagnostics have significantly enhanced the detection of causative mutations, enabling improved clinical management and genetic counseling. Emerging therapeutic approaches, including pharmacological interventions, offer promising avenues for correcting pigmentation defects.