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At least 19 recordsLinked to original sources
PubMed2026

Establishment of a human induced pluripotent stem cell line, KMUGMCi011-A, from a patient bearing a frameshift mutation in the KMT2D gene leading Kabuki syndrome 1.

Kabuki syndrome 1 is a rare genetic disorder typically characterized by facial abnormalities, cognitive impairment, developmental delay and organ dysfunction. It is caused by a loss-of-function mutation in the KMT2D gene. The peripheral blood mononuclear cells from a patient carrying frameshift mutation in the KMT2D gene were reprogrammed using the CytoTune-iPS2.0 Sendai Reprogramming Kit. This frameshift mutation results in a truncated protein. This established human induced pluripotent cell line will allow proper in vitro disease modelling of Kabuki syndrome 1.

Journal Article↗
PubMed2026

Two iPSC lines with frameshift mutations in FTSJ1 as models for X-linked non-syndromic intellectual disability.

CRISPR/Cas9 was used to introduce two different FTSJ1 frameshift mutations into an existing human male iPSC line (UMGWi004-B). No additional genomic or chromosomal changes were detected. The modified iPSC express different stem cell markers and can be induced to differentiate into cells from all three germ layers. FTSJ1 is ubiquitously expressed and mutations in this X-chromosomal gene are involved in an intellectual developmental disorder (OMIM: #309549). These cells can be used to model the disease at the cellular and organoid level in their original state or after differentiation into cell types of interest.

Journal Article↗
PubMed2026

Establishment of a Common Marmoset Lineage Carrying a Frameshift Mutation in SETD1A, a Schizophrenia Risk Gene.

Appropriate histone modifications are essential for maintaining functional chromatin structure and gene expression, and dysfunction of their regulators has been linked to a variety of diseases. Among these modifications, trimethylation of lysine 4 on histone H3 (H3K4me3) is a well-characterized epigenetic mark enriched at transcription start sites of actively transcribed genes. H3K4me3 regulates gene transcription by recruiting transcription factors, facilitating chromatin accessibility, and preventing DNA methylation. In mammals, methylation of H3K4 is catalyzed by a family of histone methyltransferases including SET domain containing 1A (SETD1A), which is primarily responsible for genome-wide deposition of H3K4me2/3. Loss-of-function variants in SETD1A, highlighting its critical role in brain development and cognitive function, are strongly associated with schizophrenia (SCZ) and other neurodevelopmental disorders, but the underlying mechanisms remain largely unclear. To better understand the epigenetic and neurobiological consequences of SETD1A dysfunction, non-human primate models can serve as a useful tool because of their close evolutionary relationship to humans and highly developed cognitive abilities. In this study, we established a genetically engineered common marmoset (Callithrix jacchus) lineage carrying a frameshift mutation in SETD1A, which is, to the best of our knowledge, the first non-human primate lineage carrying a mutation in an epigenetic regulatory gene associated with SCZ, and confirmed germline transmission of the mutant allele. In a comparison between fibroblasts derived from one SETD1A mutant and one wild-type marmoset, the mutant showed a lower SETD1A protein level, modest differences in H3K4me3 deposition, and broader differences in gene expression profiles. Although these molecular observations require validation using additional biological replicates, the establishment of this SETD1A mutant marmoset lineage provides a valuable platform for bridging molecular mechanisms with primate neurobiology and for investigating the role of epigenetic regulation in the pathophysiology of neuropsychiatric and neurodevelopmental disorders.

Animals↗
PubMed2024

Four novel mutations identified in the COL4A3, COL4A4 and COL4A5 genes in 10 families with Alport syndrome.

BACKGROUND: Alport syndrome (AS) is an inherited nephropathy caused by mutations in the type IV collagen genes. It is clinically characterized by damage to the eyes, ears and kidneys. Diagnosis of AS is hampered by its atypical clinical picture, particularly when the typical features, include persistent hematuria and microscopic changes in the glomerular basement membrane (GBM), are the only clinical manifestations in the patient. METHODS: We screened 10 families with suspected AS using whole exome sequencing (WES) and analyzed the harmfulness, conservation, and protein structure changes of mutated genes. In further, we performed in vitro functional analysis of two missense mutations in the COL4A5 gene (c.2359G > C, p.G787R and c.2605G > A, p.G869R). RESULTS: We identified 11 pathogenic variants in the type IV collagen genes (COL4A3, COL4A4 and COL4A5). These pathogenic variants include eight missense mutations, two nonsense mutations and one frameshift mutation. Notably, Family 2 had digenic mutations in the COL4A3 (p.G1170A) and UMOD genes (p.M229K). Family 3 had a digenic missense mutation (p.G997E) in COL4A3 and a frameshift mutation (p.P502L fs*151) in COL4A4. To our knowledge, four of the 11 mutations are novel mutations. In addition, we found that COL4A5 mutation relation mRNA levels were significantly decreased in HEK 293 T cell compared to control, while the cellular localization remained the same. CONCLUSIONS: Our research expands the spectrum of COL4A3-5 pathogenic variants, which is helpful for clinical and scientific research.

Humans↗
PubMed2025

Long-Read Sequencing of the MUC1 VNTR: Genomic Variation, Mutational Landscape, and Its Impact on ADTKD Diagnosis and Progression.

BACKGROUND: ADTKD-MUC1 is caused by frameshift mutations in MUC1 gene that produce a frameshifted protein (MUC1fs) toxic to kidney cells. The gene's variable number of tandem repeats (VNTR), with high GC content, makes it largely inaccessible to standard sequencing. As a result, both the reference sequence and natural variation in this region remain poorly defined, complicating mutation detection and data interpretation. Standard methods also fail to pinpoint the exact VNTR unit affected, limiting insight into mutation mechanisms and genotype-phenotype correlations. METHODS: We employed Single Molecule, Real-Time (SMRT) sequencing and characterized the genomic sequence of MUC1 in 300 individuals including 279 individuals from 143 families suspected of having ADTKD-MUC1. We compared these results to those obtained using the CLIA-approved mass spectrometry-based probe extension (PE) assay, which specifically detect the most prevalent 59dupC mutation. We correlated the structural features of the MUC1 VNTR with the rate of kidney function decline in affected individuals. RESULTS: We identified MUC1 consensus sequences for 205 unique VNTR alleles, with 9 distinct types of frameshift mutations present on 52 distinct mutated VNTR alleles. MUC1 frameshift mutations were identified in 71 of 143 families (50%) with suspected ADTKD, comprising 135 genetically affected individuals (48%). The SMRT assay exhibited complete concordance and revealed that the PE assay is capable of detecting frameshift mutations in approximately 85% of affected families. The constellation of VNTR structures supports a genotype-progression model, in which fast progressors exhibit a significantly lower number of repeat units on the wild-type allele and a higher number of repeats on the mutation-bearing allele, including an increased number of frameshifted repeat units. CONCLUSIONS: SMRT sequencing outperforms current diagnostic methods for ADTKD-MUC1 and reveals the prognostic value of VNTR structures. Although their contribution to disease progression is modest (~6% variance explained), it remains biologically and clinically meaningful.

Autosomal Dominant Tubulointerstitial Kidney Disea↗
PubMed1978

Genetic studies of acridine-induced mutants in Streptococcus pneumoniae.

The mutagenic properties of acridines on pneumococcus are described. All seven acridines tested were mutagenic at the amiA locus conferring a resistance to 10(-5) M aminopterin. The effects of quinacrine were more specifically investigated. It was observed that: mutants can be obtained only by treatment of exponentially growing cells; a sharp maximum mutagenic effect occurs at a concentration slightly lower than the bacteriostatic value; and the amount of quinacrine required to yield the maximum mutagenic effect decreases with the pH of the medium. Moreover, the number of mutants detected after quinacrine treatment varies from locus to locus. The majority of quinacrine-induced mutants are readily reverted by quinacrine, but not by nitrosoguanidine treatment. This suggests that in pneumococcus quinacrine induces mainly frameshift mutations. A further study of the revertants obtained by quinacrine treatment of quinacrine-induced mutants strengths this interpretation: most of the revertants result from a mutation at the same site; some partial revertants exhibiting an intermediate resistance to aminopterin were found to contain two very closely linked mutated sites, each mutation conferring the maximum level of resistance to aminopterin. Thus, the majority of quinacrine-induced mutants at the amiA locus of pneumococcus consists of frameshift mutations. Nearly all of the isolated mutants induced by quinacrine as well as other acridines belong to the low efficiency class of transformation. It was concluded that the mismatch resulting from the pairing between the wild type and the frameshift-containing sequence is recognized by the excision-repair system involved in the discrimination function in a way similar to that in which it recognizes mismatched base pairs between a transition mutation and the wild-type sequence.

Acridines↗
PubMed2026

A truncated COL10A1 protein causes Schmid metaphyseal chondrodysplasia via protein downregulation and impairing α1 trimer formation and secretion.

Schmid-type metaphyseal chondrodysplasia (SMCD) is primarily caused by mutations in the COL10A1 gene. This study reports a novel frameshift mutation, c.1940dup (p.Asn647Lysfs*2), identified in a Chinese SMCD pedigree. The mutation did not alter messenger RNA levels but significantly reduced COL10A1 protein expression. The mutant protein lacks the C-terminal 33 amino acids, resulting in a truncated polypeptide of 648 residues with a lower molecular weight than the wild-type protein. Degradation kinetics analysis showed no evidence of accelerated turnover. Notably, even under complete inhibition of degradation pathways, mutant protein expression remained substantially lower than that of wild-type, suggesting a potential defect in translational efficiency. Furthermore, the mutation severely disrupted the assembly of the characteristic collagen X trimer and led to markedly reduced extracellular secretion, as measured by accumulated protein levels in conditioned medium. These findings demonstrate that the c.1940dup mutation contributes to SMCD pathogenesis through coordinated mechanisms involving protein truncation, reduced expression, probable translational deficiency, and defective trimer formation and secretion, thereby revealing new potential therapeutic targets.

Osteochondrodysplasias↗
PubMed2025

LCORL and STC2 Variants Increase Body Size and Growth Rate in Cattle and Other Animals.

Natural variants can significantly improve growth traits in livestock and serve as safe targets for gene editing, thus being applied in animal molecular design breeding. However, such safe and large-effect mutations are severely lacking. Using ancestral recombination graphs, we investigated recent selection signatures in beef cattle breeds, pinpointing sweep-driving variants in the LCORL and STC2 loci with notable effects on body size and growth rate. The ACT-to-A frameshift mutation in LCORL occurs mainly in central-European cattle, and stimulates growth. Remarkably, convergent truncating mutations were also found in commercial breeds of sheep, goats, pigs, horses, dogs, rabbits, and chickens. In the STC2 gene, we identified a missense mutation (A60P) located within the conserved region across vertebrates. We validated the two natural mutations in gene-edited mouse models, where both variants in homozygous carriers significantly increase the average weight by 11%. Our findings provide insights into a seemingly recurring gene target of body size enhancing truncating mutations across domesticated species, and offer valuable targets for gene editing-based breeding in animals.

Animals↗
PubMed2026

A targetable dependency on nonsense-mediated decay for cellular homeostasis and immune control in small cell lung cancer.

Small cell lung cancer (SCLC) is one of the most aggressive malignancies, characterized by rapid metastatic dissemination and poor overall survival. Despite harboring excessive alterations, expectedly resulting in immunogenic neoantigens, patients with SCLC remain largely refractory to immunotherapy. We found abundant frameshift mutations in SCLC, regarded as highly immunogenic, counterbalanced by a hyperactive nonsense-mediated decay (NMD) pathway, responsible for frameshift-mRNA degradation. NMD activity correlated with tumor mutational burden (TMB) across cancers, suggesting that SCLC and other TMBhigh cancers may depend on NMD to limit the accumulation of mutation-derived byproducts in order to maintain cellular homeostasis and evade immune recognition. In TMBhigh SCLC models, inhibition of NMD impaired cell proliferation and induced ER stress-dependent apoptosis due to the accumulation of misfolded proteins. Genetic and pharmacological NMD inhibition in vivo effectively controlled TMBhigh tumor growth without overt toxicity. By integrating genome and transcriptome sequencing with MHC-I immunopeptidomics and functional in vitro and in vivo assays, we identified that NMD inhibition boosted neoantigen expression and presentation by tumor cells and increased T cell recognition, thus enhancing overall tumor immunogenicity and further improving immunotherapy efficacy in vivo. Our work shows that SCLC - as a TMBhigh cancer - relies on NMD for survival and immune escape, uncovering a novel TMB-dependent tractable vulnerability for this devastating disease.

Humans↗
PubMed1977

[Mutagenicity of the metabolites of the epoxide-diol pathway of safrole and its analogs. Study on Salmonella typhimurium].

Mutagenicity of the metabolites of the expoxide-diol pathway of safrole and analogues was studied on Ames' strains with Ames' method. Safrole, eugenol, eugenolmethylether, estragol, allylbenzene and 1'-hydroxysafrole, are not mutagen on TA 1535, TA 100 (point mutation) and TA 1537, TA 1538, TA 98 (frameshift mutations) without activation system. The corresponding epoxides that we have synthetized, are mutagens and inducers of point mutation in TA 1535 and TA 100. Dose-effect curves show differences between the mutagen efficiencies of these epoxides probably in relation with their electrophilic properties. On the other hand the 2', 3'-dihydro-2',3'-dihydroxisafrole was not mutagen in Ames' test. These results confirm the promutagen character of safrole and analogues and the role of the epoxides as proximate carcinogens.

Carcinogens↗
PubMed2000

Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23.

Genes causing nonsyndromic autosomal recessive deafness (DFNB12) and deafness associated with retinitis pigmentosa and vestibular dysfunction (USH1D) were previously mapped to overlapping regions of chromosome 10q21-q22. Seven highly consanguineous families segregating nonsyndromic autosomal recessive deafness were analyzed to refine the DFNB12 locus. In a single family, a critical region was defined between D10S1694 and D10S1737, approximately 0.55 cM apart. Eighteen candidate genes in the region were sequenced. Mutations in a novel cadherin-like gene, CDH23, were found both in families with DFNB12 and in families with USH1D. Six missense mutations were found in five families with DFNB12, and two nonsense and two frameshift mutations were found in four families with USH1D. A northern blot analysis of CDH23 showed a 9.5-kb transcript expressed primarily in the retina. CDH23 is also expressed in the cochlea, as is demonstrated by polymerase chain reaction amplification from cochlear cDNA.

Alleles↗
PubMed2025

Comparative Genomic Analysis of Six Mycoplasma Gallisepticum Strains: Insights into Genetic Diversity and Antibiotic Resistance.

Mycoplasma gallisepticum (MG) is a significant pathogen that causes respiratory diseases, which have had a substantial economic impact on the poultry industry. Despite the resistance of MG to antibiotics, it is imperative to identify genetic diversity in order to develop countermeasures. In this study, the genomes of six MG strains were examined to gain deeper insights into the mutations. The data pertaining to Variant Annotation and Mutation Analysis using SnpEff, along with the calculation of mutation rates as the ratio of total mutations to the length of the genomic regions analyzed, were thoroughly examined. The comprehensive evaluation yielded a total of 25,942 variants across the six strains, underscoring substantial genetic diversity. Notably, strain S6 exhibited a preponderance of frameshift mutations. A notable finding was the presence of a mutation in the MsbA gene shared by all six strains. Furthermore, five of the six strains, with the exception of strain F99 Lab, exhibited a mutation at position 5158, which impacts a multidrug transport system. Notably, strain ATCC exhibits a distinctive mutation at position 942, while strain S6 displays a unique mutation at position 6855, which is linked to efflux ABC transporter components. Furthermore, a substantial degree of genetic variation was observed among the CrmA, GapA, and vlhA genes among the various strains. High-impact changes, such as insertions and deletions, exhibited a higher frequency in CrmA, particularly in strain S6. Conversely, nonsynonymous variations demonstrated a heightened prevalence in GapA, particularly in strain F99 Lab. The vlhA gene exhibited a spectrum of effects, ranging from synonymous mutations to high-impact mutations such as stop-gains and frameshifts, particularly in strains k5111a and k4602. The functional variations observed among the strains can be attributed to these mutations, which have the potential to alter gene expression or protein function. Furthermore, substantial mutations in the dxr and rpoC genes were associated with antibiotic resistance. These mutations underscore the ongoing evolutionary adaptations of M. gallisepticum. Consequently, there is an imperative for the revision of treatment protocols and the formulation of targeted vaccines to regulate resistance within the poultry industry.

Mycoplasma gallisepticum↗
PubMed1977

Frameshift mutagenesis in bacteria by 8-methoxypsoralen (methoxalen) in the dark.

We confirm that 8-methoxypsoralen (8-MOP) in the dark induces frameshift mutations in both Escherichia coli and Salmonella typhimurium when present in adequate concentration under growth conditions. The dose response is sigmoidal with a threshold or quasi-threshold at concentrations below about 10 microgram/ml. Frameshift mutagenesis by 8-MOP in the dark is unaffected by mutations at the uvrA or uvrB genes, in contrast to base pair substitution mutagenesis by 8-MOP plus near UV light. RecA (but not recB) bacteria are hypersensitive to the growth-inhibiting action of 8-MOP in the dark and are not detectably mutagenized. The characteristics of 8-MOP dark mutagenesis are consistent with the chemical interacting in a non-covalent manner with DNA and affecting the rate of occurrence of base deletions or insertions during DNA replication. The question of extrapolation of the genetic effect of 8-MOP to man is discussed.

Darkness↗
PubMed1979

Nitrogen control in Salmonella: regulation by the glnR and glnF gene products.

The product of the glnR gene is required for nitrogen regulation of the synthesis of glutamine synthesis (Gln synthetase) [L-glutamate:ammonia ligase (ADP-forming), EC 6.3.1.2] and two periplasmic transport proteins that are subject to nitrogen control in Salmonella. Strains with mutations to loss of function of the glnR product [e.g., a strain with a Tn10 insertion or one with an ICR-induced (frameshift) mutation in glnR] have about 3% as much Gln synthetase as a fully derepressed wild-type strain and are unable to increase synthesis of this enzyme or periplasmic transport proteins in response to nitrogen limitation. The structural gene for Gln synthetase, glnA, and those for the periplasmic transport proteins are unlinked on the chromosome; thus, glnR appears to encode a diffusible positive regulatory element. Consistent with this, the mutant glnR allele is recessive to the wild-type allele with regard to expression of glnA (synthesis of Gln synthetase). Although glnR is closely linked to glnA, strains with mutations to complete loss of function of the glnR product can be distinguished from glnA strains by their ability to produce detectable Gln synthetase and to grow in the absence of glutamine. To demonstrate unequivocally that glnR is distinct from glnA, we have purified and characterized Gln synthetase from a strain with a Tn10 insertion in glnR. Because the properties of Gln synthetase from the insertion mutant, most importantly the carboxyl-terminal sequence of amino acids, are the same as those of synthetase from wild type, the Tn10 insertion cannot be in glnA (if it were, the carboxyl terminus of Gln synthetase would have to be altered); therefore we conclude that the Tn10 insertion is in a regulatory gene, glnR, which is distinct from glnA. A model for the function of the glnR product together with the previously defined glnF product in mediating nitrogen control is discussed.

Carrier Proteins↗
PubMed2025

Fe-S cluster deficiency drives small colony variant formation in persistent infections.

INTRODUCTION: Small colony variants (SCVs) of Staphylococcus aureus (S. aureus) are associated with persistent infections and poor clinical outcomes. The mechanisms driving stable SCV formation remain poorly understood, particularly concerning metabolic adaptations. This study explores the in-host evolutionary dynamics of S. aureus and identifies a novel genetic determinant linked to SCV formation. OBJECTIVES: To investigate the genetic mutations and phenotypic adaptations underlying SCV formation, with a focus on the role of a novel mutation in the sufB gene, which is critical for Fe-S cluster biosynthesis. METHODS: Sequential isolates from a patient with recurrent infections were analyzed using whole-genome sequencing, antimicrobial susceptibility testing, and functional assays. The phylogenetic relationship of the isolates was determined, and specific mutations were identified. Functional assays included aconitase and glutamate synthase activity measurements, ATP level quantification, reactive oxygen species (ROS) production, and biofilm formation assays. In vivo pathogenesis was assessed using a murine catheter infection model. RESULTS: A novel frameshift mutation in sufB was identified, disrupting Fe-S cluster biosynthesis and impairing the TCA cycle and electron transport chain, leading to reduced ATP and ROS production. This metabolic reprogramming promoted stable SCV formation, characterized by slow growth, enhanced tolerance to antibiotics and neutrophil-mediated killing, and persistent inflammation in vivo. Restoration of sufB reversed these phenotypes, confirming its pivotal role in SCV-associated persistence. CONCLUSION: sufB is a novel genetic determinant of stable SCV formation through Fe-S cluster deficiency, driving metabolic shifts that enhance immune evasion and chronic infection. Our findings highlight antibiotic stewardship and suggest potential therapeutic strategies for managing persistent SCV-associated infections.

Staphylococcus aureus↗
PubMed1976

Bacteriophage Mu-1-induced mutation to mutT in Escherichia coli.

Of approximately 10,000 independent phage Mu-1 lysogens, 3 had a mutator phenotype. One (mutation designated mut-49) resembled mutT1 in the frequency and types of mutations induced. mut-49 was mapped between leu and ace and was not separable from the Mu prophage. mut-49 was recessive and did not complement mutT1. mut-49, like mutT1, did not increase the reversion of the frameshift mutation lac Z (ICR48). mut-49 and mutT1 induced the same two classes of trpA78 revertants, indicating that mut-49 induced adenine-thymine leads to cytosine-guanine transversions. The results support previous work indicating that the mutational specificity of mutT is gene and not allele specific.

Azides↗
PubMed2026

Pleiotropic mutation in a tendril TCP gene underlies the yield-enhancing multiple-flowering trait in summer squash (Cucurbita pepo).

Crop yield is a focal point in plant breeding. Regulation of lateral budding through apical dominance was a central target of crop domestication, directly affecting crop production. The young fruits of Cucurbita pepo, summer squash, are produced on plants characterized by apical dominance and differentiation of a single flower bud per leaf axil. A single recessive mutation, mf, results in differentiation of more than one flower per leaf axil, thereby directly increasing production because of the continual day-to-day harvest of the summer squash crop. Positional cloning of the Cucurbita pepo mf (Cpmf) gene denoted a frameshift mutation in a TCP transcription factor, Cp4.1LG13g07780, as causative for the increase in axillary flowering. Cpmf is an ortholog of a tendril-development TCP gene in other cucurbits, and likewise, the recessive allele of Cpmf is associated with distorted tendril development. Gene function is context dependent, and we propose that multiple flowering is a unique pleiotropic attribute of mutation in a tendril-development gene of C. pepo. Characterization of a C. pepo collection confirmed a significant association of the Cpmf mutation with multiple flowering and showed that the mutant allele is absent in ancestral C. pepo and one of its two cultivated subspecies. The beneficial mutation occurred and was selected after the domestication of the other subspecies, during its cultivation for young fruit production. We demonstrate the discovery of a causative yield-increasing sequence variant and its practical utilization in breeding. Our findings provide a molecular target for creation of high-yielding, multiple-flowering summer squash cultivars through marker-assisted breeding or precise genome editing.

Cucurbita↗
PubMed2025

Comprehensive analysis of a novel LYST mutation in a Tunisian patient with Chediak-Higashi syndrome.

BACKGROUND: Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, recurrent infections, bleeding tendencies, and progressive neurological impairment. The syndrome is caused by mutations in the LYST gene, which plays a crucial role in lysosomal trafficking. OBJECTIVE: This study aims to characterize the molecular basis of CHS in a Tunisian patient by identifying mutations in the LYST gene and analyzing their impact on the protein function, correlating these findings with the patient's clinical presentation. METHODS: A comprehensive clinical assessment was conducted on the patient, followed by biochemical, hematological, and microbiological analyses. Additionally, LYST protein levels were quantified in the patient and their parents using an ELISA assay. Genomic DNA was extracted from the patient's blood, and Whole Exome Sequencing (WES) was performed to identify mutations in the LYST gene. The findings were confirmed through Sanger sequencing, and bioinformatic tools were employed to predict the functional consequences of the detected mutations. RESULTS: The patient presented with classical symptoms of CHS, including silver hair, hypopigmented skin, recurrent infections, and neurological decline, with an unusually late onset at 18 years. ELISA results demonstrated significantly reduced LYST levels in the patient (1.8 ng/ml) compared to heterozygous parents (7.8 ng/ml and 8.1 ng/ml) and controls (9.2 ng/ml). Genetic analysis revealed a novel homozygous deletion, c.10269_10275del (p.Gly3424SerfsTer15), in the LYST gene, leading to a frameshift mutation and premature termination of the protein. Bioinformatic analysis demonstrated that this mutation leads to the deletion of five out of sven WD40 repeats in the protein's C-terminal region, which are critical for protein-protein interactions and lysosomal trafficking. CONCLUSION: The study identifies a novel LYST mutation in a Tunisian patient with CHS, expanding the spectrum of known genetic variants associated with the disease. The findings highlight the importance of genetic screening in populations with high consanguinity and underscore the need for targeted therapies to address the molecular defects in CHS.

Adolescent↗