Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Griscelli Syndrome Type 2. Core disease mechanisms, molecular and cellular...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 18
• Snippets retrieved: 20

Relevant Papers

[1] Atypical Clinical Course of Griscelli Syndrome Type 2 With Primarily Neurologic Presentation and Adult‐Onset in a 46‐Year‐Old Male

• Authors: D. Papingi, M. Kutsche, H. Lichtenfeld, F. Kortüm, A. Abicht et al.
• Year: 2026
• Venue: American Journal of Medical Genetics Part A
• URL: https://www.semanticscholar.org/paper/66ce56a93287c3319f807deb45c5aa1a70d813a1
• DOI: 10.1002/ajmg.a.70140
• PMID: 41851022
• Summary: A 48‐year‐old patient with a 48‐year‐old patient with a neurological presentation: cerebellar dysarthria, ataxia, nystagmus, and muscle hypotonia in the lower limbs is described, cementing the clinical diagnosis of Briscelli Syndrome Type 2.
• Evidence snippets:
• Snippet 1 (score: 0.466) > Atypical Clinical Course of Griscelli Syndrome Type 2 With Primarily Neurologic Presentation and Adult‐Onset in a 46‐Year‐Old Male

[2] Griscelli syndrome Type 2: A report of rare case

• Authors: C. Kudligi, P. Bhagwat, M. Chhangte, V. Kuntoji, S. Giriyan et al.
• Year: 2017
• Venue: Clinical Dermatology Review
• URL: https://www.semanticscholar.org/paper/cf8752f4354937f622048f59c679c2b04ed123fa
• DOI: 10.4103/CDR.CDR_1_16
• Citations: 1
• Summary: A case of GS2 which was diagnosed well before the development of life-threatening HLH is reported, which is most common among three types with 11 cases reported from the Indian literature.
• Evidence snippets:
• Snippet 1 (score: 0.444) > Griscelli syndrome Type 2: A report of rare case

[3] Griscelli syndrome type 2: a novel mutation in RAB27A gene with different clinical features in 2 siblings: a diagnostic conundrum

• Authors: K. Mishra, S. Singla, Suvasini Sharma, R. Saxena, V. Batra
• Year: 2014
• Venue: Korean Journal of Pediatrics
• URL: https://www.semanticscholar.org/paper/e53db24ce1a1baba8017874591ca89620e7de6ce
• DOI: 10.3345/kjp.2014.57.2.91
• PMID: 24678334
• PMCID: 3965801
• Citations: 23
• Summary: The atypical features of Griscelli syndrome type 2 in these cases are a novel mutation, isolated neurological involvement in one sibling, association with erythema nodosum, and 2 distinct clinical presentations in siblings with the same genetic mutation.
• Evidence snippets:
• Snippet 1 (score: 0.423) > Griscelli syndrome type 2: a novel mutation in RAB27A gene with different clinical features in 2 siblings: a diagnostic conundrum
• Snippet 2 (score: 0.369) > Griscelli syndrome type 2 (GS2) is a rare autosomal recessive disease caused by mutations in the RAB27A gene. It is characterized by cutaneous hypopigmentation, immunodeficiency, and hemophagocytic lymphohistiocytosis. We describe 2 brothers who had GS2 with clinically diverse manifestations. The elder brother presented with a purely neurological picture, whereas the younger one presented with fever, pancytopenia, hepatosplenomegaly, and erythema nodosum. Considering that cutaneous hypopigmentation was a common feature between the brothers, genetic analysis for Griscelli syndrome was performed. As the elder sibling had died, mutation analysis was only performed on the younger sibling, which revealed a novel homozygous mutation in the RAB27A gene on chromosome 15 showing a single-base substitution (c.136T>A p.F46I). Both parents were heterozygous for the same mutation. This confirmed the diagnosis of GS2 in the accelerated phase in both siblings. The atypical features of GS2 in these cases are a novel mutation, isolated neurological involvement in one sibling, association with erythema nodosum, and 2 distinct clinical presentations in siblings with the same genetic mutation.

[4] Molecular Genetics of Bartter Syndrome: Bridging Genotype–Phenotype Correlations and Precision Therapeutics

• Authors: Lina Zhu, Yang Li, Yiyao Bao
• Year: 2026
• Venue: Current Issues in Molecular Biology
• URL: https://www.semanticscholar.org/paper/a5e1ddccfa7d333834c4d32be123c71bfd573f83
• DOI: 10.3390/cimb48040422
• PMID: 42042082
• PMCID: 13114623
• Summary: A comprehensive framework to provide a comprehensive framework to facilitate precise diagnosis and individualized treatment strategies, ultimately advancing precision medicine in the management of Bartter syndrome is provided.
• Evidence snippets:
• Snippet 1 (score: 0.410) > Molecular genetic research on Bartter syndrome has made remarkable strides, elucidating the principal BS genes SLC12A1, KCNJ1, CLCNKB, BSND, and MAGED2 and their corresponding protein defects, thereby refining the molecular framework of disease classification while separating CaSR-associated Bartter-like disease from the core canonical BS spectrum. This progress has significantly deepened our understanding of the underlying pathophysiology and provided an essential framework for correlating genotypes with clinical phenotypes. However, the intricate relationship between genetic mutations and clinical manifestations remains complex and multifaceted, reflecting the profound heterogeneity of the syndrome. Addressing these diagnostic challenges and refining disease classification beyond traditional clinical criteria requires an integrative approach that seamlessly balances high-throughput sequencing technologies with rigorous functional studies. > The mechanisms by which these genetic mutations lead to protein dysfunction are diverse, encompassing critical defects in protein expression, impaired membrane localization, and direct functional impairments. Notably, aberrant protein folding, endoplasmic reticulum-associated degradation (ERAD), and splicing abnormalities have emerged as critical pathogenic pathways. These mechanistic insights not only enhance our fundamental understanding of the disease but also highlight highly promising therapeutic targets. While current treatments remain predominantly symptomatic, focusing primarily on managing electrolyte imbalances and associated complications, they inherently fail to address the underlying molecular defects driving the disease. > The precise identification of specific molecular defects opens innovative avenues for the development of targeted interventions aimed at correcting or compensating for specific protein abnormalities. For instance, molecular chaperones that assist in protein folding, agents that modulate aberrant splicing, and future gene-based strategies represent important experimental directions for mechanism-based therapy. Consequently, the future of Bartter syndrome management may increasingly move toward precision medicine tailored to the molecular pathology of individual patients. However, the transition from concept to clinical implementation will require substantial additional functional, translational, and trial-level evidence. Such mechanism-based strategies promise not only to alleviate clinical symptoms but to fundamentally modify disease progression, thereby drastically improving long-term prognosis and quality of life for patients.

[5] Personalized Medicine: The Future of Health Care

• Authors: A. Meiliana, Nurrani Mustika Dewi, A. Wijaya
• Year: 2016
• Venue: The Indonesian Biomedical Journal
• URL: https://www.semanticscholar.org/paper/02edaa39ecdab3dd64c077e71b14398b94beb742
• DOI: 10.18585/inabj.v8i3.271
• Citations: 9
• Summary: Personalized medicine seeks to use advances in knowledge about genetic factors and biological mechanisms of disease coupled with unique considerations of an individual’s patient care needs to make health care more safe and effective.
• Evidence snippets:
• Snippet 1 (score: 0.399) > (98,170,171) The genetic cardiomyopathies present a window to cardiac pathophysiology when discrete cellular pathways are disrupted. Over the past decades, the role of numerous proteins in triggering cardiomyopathy and hence HF has finally become clear. Despite the genetic complexity, direct application of genetic testing is now a mainstay in managing affected families, and scientifically and clinically useful themes are emerging that should lead to improved treatment.( 95) > Investigations of rare monogenic disorders of heart rhythm has elucidated the fundamental molecular and genetic mechanisms of sickle cell disease. After identification of more than 25 causal genes, there remain many subjects with inherited arrhythmia susceptibility but do not have mutations, this suggests that there is still other genes left unidentified. Newer strategies such as exome and WGS may be valuable to uncover additional molecular etiologies. Efforts to understand mechanisms responsible for incomplete penetrance, including identification of modifier genes, will also contribute to deciphering the complex relationships between genotype and phenotype. (97) In diabetes, personalized medicine refers to utilize the patients specific characters for most effective diagnostic or treatment strategies. These include individual behavioral and phenotypic features, standard clinical laboratory findings, and gene sequences and other molecular markers.( 172) Diabetes mellitus has long been recognized to be a complex, heterogeneous disorder, especially in type 2 diabetes patients with substantial variability in genetic risk factors, underlying pathogenic mechanisms, and clinical features. Therefore it represents a human disease that gains a substantial benefit from personalized approaches to treatment. Nevertheless, patients with type 2 diabetes often are treated similarly, with little consideration of individual characteristics that might affect clinical outcome and therapeutic response.(173) Both type 1 and type 2 diabetes are thought to be complex diseases, which means they need the interplay of numerous susceptibility and protective genes, acting in concert with negative and positive environmental factors to be developed. (174) Type 2 diabetes typically is characterized by a combination of abnormalities in both insulin secretion and responsiveness, plus a more gradual and less extensive loss of β-cell secretory capacity than occurs in type 1 diabetes.

[6] Griscelli syndrome: a diagnostic challenge of a rare disease: a case report

• Authors: Sedra Abu Ghedda, Sedra Alkadamani, R. Sabouni, Jaber Mahmoud
• Year: 2024
• Venue: Annals of Medicine and Surgery
• URL: https://www.semanticscholar.org/paper/6ea66eea9c221a980c5817e49865f26227d0787b
• DOI: 10.1097/MS9.0000000000002462
• PMID: 39359785
• PMCID: 11444549
• Citations: 2
• Influential citations: 1
• Summary: The challenges faced in the diagnosis of a patient with Griscelli syndrome who presents with neurological symptoms followed by immunological deficits are detailed, with a focus on the presence of HLH.
• Evidence snippets:
• Snippet 1 (score: 0.391) > Griscelli syndrome: a diagnostic challenge of a rare disease: a case report
• Snippet 2 (score: 0.372) > • Griscelli syndrome (GS) is a rare autosomal recessive genetic disorder that causes different presentations according to its type. • The diagnosis of GS is usually established through genetic analysis upon clinical suspicion. • Access to such tests in war zones might be limited. > • The clinical manifestations, along with the age of presentation, play a crucial role in distinguishing between GS types. • Early detection and diagnosis can help increase the quality of life. > In this case report, we discuss the challenges in distinguishing the type of GS in a 7-month-old girl who presented with clinical features indicative of both type 1 and type 2 GS.

[7] Griscelli syndrome-type 2 in twin siblings: case report and update on RAB27A human mutations and gene structure.

• Authors: I. Meschede, T. O. Santos, T. Izidoro-Toledo, J. Gurgel-Gianetti, E. M. Espreafico
• Year: 2008
• Venue: Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas
• URL: https://www.semanticscholar.org/paper/6b3bcf98817f9023d79476ad135808363fb4055a
• DOI: 10.1590/S0100-879X2008001000002
• PMID: 19030707
• Citations: 43
• Influential citations: 3
• Summary: The diagnosis of GS2 in 3-year-old twin siblings is reported, with silvery-gray hair, immunodeficiency, hepatosplenomegaly and secondary severe neurological symptoms that culminated in multiple organ failure and death.
• Evidence snippets:
• Snippet 1 (score: 0.391) > Griscelli syndrome-type 2 in twin siblings: case report and update on RAB27A human mutations and gene structure.

[8] The Lamin Proteins in Nuclear Structure, Functions, and Laminopathies

• Authors: Gan Zhao, Ziheng Chen, Caifeng Yang, Mingzheng Liu, Weiyong Wang et al.
• Year: 2026
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/9db8088d893cc5c3de80d3afda68b52e1cf501fc
• DOI: 10.3390/cells15121051
• PMID: 42346079
• PMCID: 13296569
• Citations: 1
• Summary: Collectively, studies of lamin protein function reveal how the nucleus maintains its structures and functions, while studies of laminopathies demonstrate how nuclear dysfunction drives systemic disease and points toward mechanism-based therapies.
• Evidence snippets:
• Snippet 1 (score: 0.390) > Laminopathies represent a clinically diverse class of human diseases caused by mutations in genes encoding components of the nuclear lamina and associated nuclear envelope proteins. Here, we summarize the mutation sites, phenotypes, and underlying molecular mechanisms of laminopathies (Table 1). Although mutations in LMNA account for the majority of reported cases, disease-causing alterations in B-type lamins, particularly LMNB1, as well as mutations in other nuclear envelope proteins, also give rise to distinct laminopathy phenotypes [13,77]. The pathogenesis of laminopathies is explained through several interconnected mechanistic frameworks. The classical structural hypothesis attributes disease to compromised nuclear integrity and impaired mechanical signaling, leading to stress-induced cellular damage, particularly in striated muscle tissues [23]. In contrast, the "gene expression hypothesis" emphasizes that lamin mutations disrupt chromatin organization and intracellular signaling pathways, thereby altering transcriptional programs [12,119]. More recently, these perspectives have been integrated with models highlighting cellular senescence, stem cell exhaustion, and chronic inflammation as additional pathogenic contributors, especially in progeroid syndromes [112]. Current evidence suggests that these mechanisms are not mutually exclusive but operate within an interconnected and synergistic network that drives disease progression [120]. > In laminopathies, mutations affect structural components present in nearly all nucleated cells. Nevertheless, laminopathies exhibit marked tissue-specific vulnerability, predominantly affecting striated muscle, adipose tissue, peripheral nerves, or, in some cases, causing systemic premature aging [12,15]. This tissue selectivity likely arises from the interaction between a specific lamin mutation and the distinct mechanical demands, transcriptional programs, and developmental context of individual tissues [15,119]. Consequently, although laminopathies share common molecular roots, their clinical manifestations are highly system-oriented. > For this reason, laminopathies are conventionally classified according to the primary tissue or organ system affected, despite substantial phenotypic overlap among categories [14]. This classification provides a clinically practical framework while acknowledging that shared pathogenic mechanisms underlie seemingly distinct disease entities. > Striated muscle laminopathies represent a major disease category.

[9] GRISCELLI SYNDROME TYPE 2: THE FIRST REPORTED CASE OF COMPOUND HETEROZYGOUS MUTATION IN RAB 27 A GENE FROM INDIA

• Authors: Nishad Dhakate, Manjit Rajput
• Year: 2019
• Venue: Indian Journal of Case Reports
• URL: https://www.semanticscholar.org/paper/b66d9e0b7a41e279d6c6fb46f7a7d2f8b19ce891
• DOI: 10.32677/ijcr.2019.v05.i06.002
• Citations: 1
• Summary: A 3-year-old female with pyrexia, silvery hair, lymphadenopathy, hepatosplenomegaly, and hemophagocytosis is described and a novel compound heterozygous mutation in the RAB 27A gene is found.
• Evidence snippets:
• Snippet 1 (score: 0.383) > Griscelli syndrome (GS) is a rare autosomal recessive disorder resulting in pigmentary dilution of the skin and hair with variable phenotypes depending upon the underlying genetic mutation. Mutations in 3 distinct genes MYO5A, RAB27A, MLPH are responsible for 3 subtypes (GS1, GS2, and GS3) of GS respectively. Griscelli syndrome type 2 (GS-2) is a rare autosomal recessive disease. It commonly presents with hemophagocytic lymphohistiocytosis (HLH) and recurrent infections due to immunodeficiency. We describe a 3-year-old female with pyrexia, silvery hair, lymphadenopathy, hepatosplenomegaly, and hemophagocytosis. We found a novel compound heterozygous mutation in the RAB 27A gene. She succumbed despite being on dexamethasone and septran prophylaxis. This case spreads awareness about this rare potentially fatal disease, as a high index of suspicion is required for prompt diagnosis and treatment. Early bone marrow transplant is the only curative treatment for GS-2.

[10] Molecular genetic basis of epidermolysis bullosa

• Authors: Y. Kotalevskaya, V. Stepanov
• Year: 2023
• Venue: Vavilov Journal of Genetics and Breeding
• URL: https://www.semanticscholar.org/paper/720cbefbd0435504a6ed670ccf4f491dfbd3f143
• DOI: 10.18699/VJGB-23-04
• PMID: 36923479
• PMCID: 10009482
• Citations: 9
• Influential citations: 3
• Summary: The study of clinical, genetic and ultrastructural changes in EB has significantly expanded the understanding of the natural history of the disease and supplemented the data on genotype-phenotype correlations, promotes the search and study of epigenetic and non-genetic disease modifier factors, and also allows developing approaches to radical treatment of the Disease.
• Evidence snippets:
• Snippet 1 (score: 0.381) > Epidermolysis bullosa (EB) is an inherited disorder of skin fragility, caused by mutations in a large number of genes associated with skin integrity and dermal-epidermal adhesion. Skin fragility is manifested by a decrease in resistance to external mechanical influences, the clinical signs of which are the formation of blisters, erosions and wounds on the skin and mucous membranes. EB is a multisystemic disease and characterized by a wide phenotypic spectrum with extracutaneous complications in severe types, besides the skin and mucous membranes, with high mortality. More than 30 clinical subtypes have been identified, which are grouped into four main types: simplex EB, junctional EB, dystrophic EB and Kindler syndrome. To date, pathogenic variants in 16 different genes are associated with EB and encode proteins that are part of the skin anchoring structures or are signaling proteins. Genetic mutations cause dysfunction of cellular structures, differentiation, proliferation and apoptosis of cells, leading to mechanical instability of the skin. The formation of reduced proteins or decrease in their level leads mainly to functional disorders, forming mild or intermediate severe phenotypes. Absent protein expression is a result of null genetic variants and leads to structural abnormalities, causing a severe clinical phenotype. For most of the genes involved in the pathogenesis of EB, certain relationships have been established between the type and position of genetic variant and the severity of the clinical manifestations of the disease. Establishing an accurate diagnosis depends on the correlation of clinical, genealogical and immunohistological data in combination with molecular genetic testing. In general, the study of clinical, genetic and ultrastructural changes in EB has significantly expanded the understanding of the natural history of the disease and supplemented the data on genotype-phenotype correlations, promotes the search and study of epigenetic and non-genetic disease modifier factors, and also allows developing approaches to radical treatment of the disease. New advances of sequencing technologies have made it possible to describe new phenotypes and study their genetic and molecular mechanisms. This article describes the pathogenetic aspects and genes that cause main and rare syndromic subtypes of EB.

[11] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

• Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
• Year: 2025
• Venue: Journal of Veterinary Internal Medicine
• URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
• DOI: 10.1111/jvim.70139
• PMID: 40492724
• PMCID: 12150350
• Citations: 2
• Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.375) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[12] Griscelli syndrome.

• Authors: A. K. Malhotra, G. Bhaskar, Mousmee Nanda, Madhulika Kabra, M. K. Singh et al.
• Year: 2020
• Venue: Journal of the American Academy of Dermatology
• URL: https://www.semanticscholar.org/paper/582d09e0fad8ecf0d89a6f2c1cb5d4db9c4ac681
• DOI: 10.1016/j.jaad.2005.11.1056
• PMID: 16844525
• Citations: 55
• Influential citations: 7
• Summary: A 4-month-old child had silvery gray hair, light-colored skin, recurrent chest infections, hepatosplenomegaly, and episodes of pancytopenia and hemophagocytosis in the liver, spleen, and bone marrow, and Griscelli syndrome was diagnosed.
• Evidence snippets:
• Snippet 1 (score: 0.372) > Griscelli syndrome.

[13] Discovering cell types underlying rare disease phenotypes using scRNA-seq data from non-diseased tissues

• Authors: Jorge Novoa, F. Pazos, M. Chagoyen
• Year: 2025
• Venue: bioRxiv
• URL: https://www.semanticscholar.org/paper/c038b1472f7b42b58e9068eae4b0b0bf3970657e
• DOI: 10.64898/2025.12.09.693155
• Summary: Applied across diverse tissues and phenotypes, Cell4Rare was validated against literature-based associations and highlights the potential of computational analyses of non-diseased scRNA-seq data to uncover the cellular basis of rare disease phenotypes, paving the way for improved diagnostics and therapeutic strategies.
• Evidence snippets:
• Snippet 1 (score: 0.369) > Rare diseases, despite their individual low prevalence, collectively affect millions worldwide and pose persistent challenges for both diagnosis and treatment. The majority of these conditions have a genetic basis, with mutations that disrupt molecular and cellular pathways, ultimately manifesting as distinct and often severe phenotypes. Experimental approaches such as CRISPR-Cas9 gene editing, animal models, patient-derived iPSCs, and in vitro functional assays have become indispensable tools for validating the pathogenicity of specific variants and establishing the molecular and cellular pathways disrupted (MacArthur et al., 2014). These strategies provide critical insights into disease etiology by enabling the direct interrogation of gene function and phenotype. However, they are often limited by high costs, extended timelines, and scalability challenges-particularly in the context of rare diseases, where patient samples and resources are scarce. These limitations underscore the urgent need for robust, scalable computational tools that make use of the more abundant healthy omics data to facilitate the discovery and understanding of rare disease-causing mechanisms. > A major obstacle in rare disease research is determining the specific cellular contexts in which pathogenic genetic variants exert their effects. This is especially challenging given that many rare disease-associated genes are broadly expressed across tissues but lead to phenotypes that are restricted to a small subset of cell types (Feiglin et al., 2017). Pinpointing these relevant cellular targets is crucial for understanding disease mechanisms and for designing effective, targeted therapies. Recent advances in single-cell transcriptomics, along with growing databases of genotype-phenotype associations, offer an unprecedented opportunity to study gene activity at cellular resolution. Yet, for most rare diseases-many of which have pediatric onset-single-cell data from affected individuals remain unavailable, making traditional case-control approaches impractical. > In this context, computational methods that extract mechanistic insights from single-cell data derived from non-diseased tissues offer a valuable alternative. These approaches can help infer the cellular consequences of genetic alterations and guide the selection of the most relevant experimental systems for downstream validation.

[14] Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

• Authors: I. Condò
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/6aece75e6947f102b657851b74e8b96df5e654c1
• DOI: 10.3390/ijms23126525
• PMID: 35742964
• PMCID: 9223693
• Citations: 19
• Influential citations: 2
• Summary: A rare disease is defined by its low prevalence in the general population and its presence in a very small number of people.
• Evidence snippets:
• Snippet 1 (score: 0.369) > The selective expression or the particular role of specific genes in a single tissue explains the appearance of organ-specific inherited diseases. This is the case of genetic disorders of the kidney, which include dominant and recessive forms of cystic diseases, and renal tubulopathies. Mutations in polycystin-1 (PKD1) or -2 (PKD2) genes lead to autosomaldominant polycystic kidney disease (ADPKD), whose gender-dependent phenotype was analyzed in the study by Talbi et al. [9]. These results, obtained in mice lacking PKD1 expression, show the involvement of intracellular Ca2+ levels in the more severe phenotype affecting male ADPKD animals. Altogether, identification of the molecular mechanisms underlying enhanced Ca2+ signaling and proliferation in cells from male kidneys may contribute to develop novel therapeutics for ADPKD [9]. The autosomal-recessive form of polycystic kidney disease (ARPKD) mostly arises from defects in the gene named polycystic kidney and hepatic disease 1 (PKHD1), whereas a minority of cases is linked to a second causative gene DZIP1L. To examine the still unclear molecular pathophysiology of ARPKD, Cordido et al. recapitulate known molecular disease mechanisms and possible therapeutic approaches, from cellular and animal models to clinical trials [10]. The knowledge of ARPKD pathogenic pathways, involving the epidermal growth factor receptor (EGFR) axis, the production of adenylyl cyclase adenosine 3 ,5 -cyclic monophosphate (cAMP) and the activation of several protein kinases, begins to stimulate possible pharmacological interventions [10]. Inherited loss of function in various electrolyte transport proteins located along the nephron leads to two types of kidney tubulopathy with overlapping clinical symptoms: Gitelman and Bartter syndromes. The review by Nuñez-Gonzalez et al. aims to explain the different molecular basis of these difficult to diagnose monogenic syndromes. Moreover, the authors provide an overview of current therapeutic approaches and highlight the presence of common and specific options for Gitelman and Bartter patients [11].

[15] Molecular insights into the premature aging disease progeria

• Authors: Sandra Vidak, R. Foisner
• Year: 2016
• Venue: Histochemistry and Cell Biology
• URL: https://www.semanticscholar.org/paper/60fb3b46bb7e42d5d08cc3b7cbc783b118300c31
• DOI: 10.1007/s00418-016-1411-1
• PMID: 26847180
• PMCID: 4796323
• Citations: 107
• Influential citations: 4
• Summary: Changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.368) > The number of molecular biological studies aiming at the identification of lamin-mediated molecular disease mechanisms involved in HGPS increased tremendously following the surprising discovery that LMNA is causally linked to the premature aging disease HGPS in 2003. Despite numerous cellular pathways that were identified to be affected by the expression of the mutant lamin A protein (Fig. 2), the mechanistic details behind these effects are still unclear in most cases. Knowledge based on what was already known on lamin biology before the protein was linked to HGPS and findings on novel roles of lamins in diverse pathways in recent years allowed the launch of translational studies and the efficient search for drug targets and therapeutic approaches within a short time period. The results of the first clinical trials taught us that some improvements of the disease phenotypes can be achieved by FTI treatment, but they also made clear that we need a much better understanding of the underlying disease mechanisms to be able to tackle specific aspects of the disease in a more focused approach. It will also be important to elucidate which of the numerous pathways found to be impaired in HGPS are most relevant for and causally involved in the pathologies, and which ones are just bystanders.

[16] Rab proteins and Rab-associated proteins: major actors in the mechanism of protein-trafficking disorders

• Authors: L. Corbeel, K. Freson
• Year: 2008
• Venue: European Journal of Pediatrics
• URL: https://www.semanticscholar.org/paper/2709c3a25387785aacd95130273ff8a44d2f2966
• DOI: 10.1007/s00431-008-0740-z
• PMID: 18463892
• PMCID: 2413085
• Citations: 112
• Influential citations: 5
• Summary: Although protein-trafficking disorders are clinically heterogeneous and represented in almost every subspeciality of pediatrics, the identification of common pathogenic mechanisms may provide a better diagnosis and management of patients with still unknown Rab cycle defects and stimulate the development of therapeutic agents.
• Evidence snippets:
• Snippet 1 (score: 0.366) > Ras-associated binding (Rab) proteins and Rab-associated proteins are key regulators of vesicle transport, which is essential for the delivery of proteins to specific intracellular locations. More than 60 human Rab proteins have been identified, and their function has been shown to depend on their interaction with different Rab-associated proteins regulating Rab activation, post-translational modification and intracellular localization. The number of known inherited disorders of vesicle trafficking due to Rab cycle defects has increased substantially during the past decade. This review describes the important role played by Rab proteins in a number of rare monogenic diseases as well as common multifactorial human ones. Although the clinical phenotype in these monogenic inherited diseases is highly variable and dependent on the type of tissue in which the defective Rab or its associated protein is expressed, frequent features are hypopigmentation (Griscelli syndrome), eye defects (Choroideremia, Warburg Micro syndrome and Martsolf syndrome), disturbed immune function (Griscelli syndrome and Charcot–Marie–Tooth disease) and neurological dysfunction (X-linked non-specific mental retardation, Charcot–Marie–Tooth disease, Warburg Micro syndrome and Martsolf syndrome). There is also evidence that alterations in Rab function play an important role in the progression of multifactorial human diseases, such as infectious diseases and type 2 diabetes. Rab proteins must not only be bound to GTP, but they need also to be ‘prenylated’—i.e. bound to the cell membranes by isoprenes, which are intermediaries in the synthesis of cholesterol (e.g. geranyl geranyl or farnesyl compounds). This means that isoprenylation can be influenced by drugs such as statins, which inhibit isoprenylation, or biphosphonates, which inhibit that farnesyl pyrophosphate synthase necessary for Rab GTPase activity. Conclusion: Although protein-trafficking disorders are clinically heterogeneous and represented in almost every subspeciality of pediatrics, the identification of common pathogenic mechanisms may provide a better diagnosis and management of patients with still unknown Rab cycle defects and stimulate the development of therapeutic agents.

[17] Tubular Aggregate Myopathies: Genetic Heterogeneity and Diverse Clinical Features Converging on Calcium Dysregulation

• Authors: Matteo Serano, F. Fiore, Vincenzo Sorrentino, Daniela Rossi
• Year: 2026
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/c53accfaacb913a69aeeb832222593ca90afabeb
• DOI: 10.3390/cells15070635
• PMID: 41972723
• PMCID: 13072200
• Citations: 2
• Summary: Highlights TAM is an inherited muscle disorder caused by STIM1 and ORAI1 mutations that disrupt calcium entry, leading to tubular aggregates and muscle dysfunction. Its overlap with Stormorken syndrome suggests a disease continuum. Although the genetics are known, mechanisms behind aggregate formation and multisystem features remain unclear, highlighting the need for deeper insight and targeted therapies. What are the main findings? Genetics and Pathogenesis: Tubular aggregate myopathy (TAM)...
• Evidence snippets:
• Snippet 1 (score: 0.365) > , hypocalcemia, hyposplenism, and ichthyosis, thereby resulting in a clinical picture that overlaps with symptoms of Stormorken (STRMK) syndrome. Considerable heterogeneity exists in age of onset, severity, and extra-muscular involvement, suggesting that TAM and STRMK represent a continuum rather than distinct entities. Histopathological hallmarks include TAs staining positive for SR proteins and displaying a honeycomb-like ultrastructure, consistent with aberrant SR remodeling. Mutations in genes encoding key regulators of store-operated calcium entry (SOCE), including STIM1 and ORAI1 have been identified as major contributors to TAM and its broader clinical spectrum, which encompasses STRMK syndrome, whereas mutations in CASQ1 and RYR1, have been described in only a minority of patients. Despite advances in delineating the genetic and molecular basis of TAM, key questions remain regarding the mechanisms that drive TAs formation and translate Ca2+ dysregulation into muscle dysfunction and multisystem disease. Understanding the molecular mechanisms underlying TAM and STRMK syndrome is crucial for developing targeted therapies. Moreover, further research is needed to elucidate additional pathways involved in disease progression and to refine genotype–phenotype correlations. This review summarizes current knowledge on the genetics, pathophysiology, clinical features, and diagnostic hallmarks of TAM, with particular emphasis on the role of Ca2+ homeostasis.

[18] Therapies for Mitochondrial Disease: Past, Present, and Future

• Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R. Thorburn, S. Rahman et al.
• Year: 2025
• Venue: Journal of Inherited Metabolic Disease
• URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
• DOI: 10.1002/jimd.70065
• PMID: 40714961
• PMCID: 12301291
• Citations: 13
• Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.365) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

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