BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) results from mutations in various genes, including REN, UMOD, MUC1, and HNF1B. ADTKD due to REN mutations (ADTKD-REN) is often characterized as a proteinopathy that triggers the endoplasmic reticulum stress (ERS) cascade, potentially sharing similarities with ADTKD-UMOD and ADTKD-MUC1 at the cellular level. This study, inspired by a patient harboring a W17R mutation, investigates ERS activation by this mutation alongside two other renin variants, W10R and L381P.
METHODS: We established stable cell lines expressing both wild-type and mutated renin forms (W17R, W10R, and L381P). Using luciferase reporter assays, RT-qPCR, and confocal microscopy, we evaluated ERS activation, determined the cellular localization of the renin variants, and characterized the mitochondrial network in the W17R line.
RESULTS: The L381P line exhibited ERS activation, including transcriptional upregulation of MANF and CRELD2. No ERS activation was observed in the W17R line, while the W10R line exhibited intermediate characteristics. Notably, the W17R variant was misrouted to the mitochondria resulting in changes of the mitochondrial network organisation.
CONCLUSIONS: ERS activation is not a universal response to different renin mutations in ADTKD-REN. The pathogenesis of the W17R mutation may involve mitochondrial dysfunction rather than the ER pathway, albeit further research is needed to substantiate this hypothesis fully. Testing CRELD2 and MANF as targeted therapy markers for a specific subgroup of ADTKD-REN patients is recommended. Additionally, fludrocortisone treatment has shown efficacy in stabilizing the renal function of our patient over a four-year period without significant side effects.

Cranio-lenticulo-sutural dysplasia (CLSD, OMIM #607812) is a rare genetic condition characterized by late-closing fontanels, skeletal defects, dysmorphisms, and congenital cataracts that are caused by bi-allelic or monoallelic variants in the SEC23A gene. Autosomal recessive inheritance (AR-CLSD) has been extensively documented in several cases with homozygous or compound heterozygous variants in SEC23A, whereas autosomal dominant inheritance (AD-CLSD) involving heterozygous inherited variants has been reported just in three patients. The SEC23A gene encodes for one of the main components of a protein coat complex known as coat-protein-complex II (COPII), responsible for the generation of the envelope of the vesicles exported from the endoplasmic reticulum (ER) toward the Golgi complex (GC). AR-CLSD and AD-CLSD exhibit common features, although each form also presents distinctive and peculiar characteristics. Herein, we describe a rare case of a 10-year-old boy with a history of an anterior fontanel that closed only at the age of 9. The patient presents with short proportionate stature, low weight, and neurological impairment, including intellectual disability, global developmental delay, abnormal coordination, dystonia, and motor tics, along with dysmorphisms such as a wide anterior fontanel, hypertelorism, frontal bossing, broad nose, high-arched palate, and micrognathia. Trio clinical exome was performed, and a de novo heterozygous missense variant in SEC23A (p.Arg716Cys) was identified. This is the first reported case of CLSD caused by a de novo heterozygous missense variant in SEC23A presenting specific neurological manifestations never described before. For the first time, we have conducted a comprehensive phenotype-genotype correlation using data from our patient and the eight most well-documented cases in the literature. Our work has allowed us to identify the main specific and characteristic signs of both forms of CLSD (AR-CLSD, AD CLSD), offering valuable insights that can guide physicians in the diagnostic process. Notably, detailed descriptions of neurological features such as intellectual disability, global developmental delay, and motor impairment have not been documented before. Furthermore, our literature overview is crucial in the current landscape of CLSD due to the absence of guidelines for the clinical diagnosis and proper follow-up of these patients, especially during childhood.

Intracellular calcium (Ca2+) is an essential second messenger in eukaryotic cells regulating numerous cellular functions such as contraction, secretion, immunity, growth, and metabolism. Ca2+ signaling is also a key signal transducer in the intrinsic apoptosis pathway. The store-operated Ca2+ entry pathway (SOCE) is ubiquitously expressed in eukaryotic cells, and is the primary Ca2+ influx pathway in non-excitable cells. SOCE is mediated by the endoplasmic reticulum Ca2+ sensing STIM proteins, and the plasma membrane Ca2+-selective Orai channels. A growing number of studies have implicated SOCE in regulating cell death primarily via the intrinsic apoptotic pathway in a variety of tissues and in response to physiological stressors such as traumatic brain injury, ischemia reperfusion injury, sepsis, and alcohol toxicity. Notably, the literature points to excessive cytosolic Ca2+ influx through SOCE in vulnerable cells as a key factor tipping the balance towards cellular apoptosis. While the literature primarily addresses the functions of STIM1 and Orai1, STIM2, Orai2 and Orai3 are also emerging as potential regulators of cell death. Here, we review the functions of STIM and Orai proteins in regulating cell death and the implications of this regulation to human pathologies.

BACKGROUND: Secretory myoepithelial carcinomas (SMCA) are rare, mucinous, signet ring predominant tumors with primitive myoepithelial features. While many mucinous salivary gland tumors have now been molecularly characterized, key drivers in SMCA have yet to be elucidated. Recently, NKX3.1, a homeodomain transcription factor implicated in salivary mucous acinar development was also shown in a subset of salivary mucinous neoplasms, salivary intraductal papillary mucinous neoplasms (SG-IPMN). To date, NKX3.1 expression has not been characterized in other mucinous salivary lesions. Here, we report molecular and extended immunophenotypic findings in SMCA and NKX3.1 expression in the context of other head and neck lesions.
METHODS: We retrieved 4 previously reported SMCA, performed additional immunohistochemical and targeted next-generation sequencing (NGS). We also investigated the use of NKX3.1 as a marker for SMCA in the context of its prevalence and extent (using H-score) in a mixed cohort of retrospectively and prospectively tested head and neck lesions (n = 223) and non-neoplastic tissues (n = 66).
RESULTS: NKX3.1 positivity was confirmed in normal mucous acini as well as in mucous acinar class of lesions (5/6, mean H-score: 136.7), including mucinous adenocarcinomas (3/4), SG-IPMN (1/1), and microsecretory adenocarcinoma (MSA) (1/1). All SMCA were positive. Fluorescence in situ hybridization for SS18 rearrangements were negative in all successfully tested cases (0/3). NGS was successful in two cases (cases 3 and 4). Case 3 demonstrated a PTEN c.655C>T p.Q219* mutation and a SEC16A::NOTCH1 fusion while case 4 (clinically aggressive) showed a PTEN c.1026+1G>A p.K342 splice site variant, aTP53 c.524G>A p.R175H mutation and a higher tumor mutation burden (29 per Mb). PTEN immunohistochemical loss was confirmed in both cases and a subset of tumor cells showed strong (extreme) staining for P53 in Case 4.
CONCLUSIONS: Despite a partial myoepithelial phenotype, SMCA, along with mucinous adenocarcinomas/SG-IPMN and MSA, provisionally constitute a mucous acinar class of tumors based on morphology and NKX3.1 expression. Like salivary mucinous adenocarcinomas/SG-IPMN, SMCA also show alterations of the PTEN/PI3K/AKT pathway and may show progressive molecular alterations. We document the first extramammary tumor with a SEC16A::NOTCH1 fusion.

UNASSIGNED: Amyotrophic lateral sclerosis is a neurodegenerative disease with wide variation of genetics associated with it. Among the different genes described, mutation in TFG is a rare finding in amyotrophic lateral sclerosis.
UNASSIGNED: A 35 years old right-handed male presenting with ipsilateral weakness was diagnosed with amyotrophic lateral sclerosis. He was found to have missense variant of TFG with uncertain significance on exome sequencing.
UNASSIGNED: The genetics involved in amyotrophic lateral sclerosis is ever-evolving. The identification of new TFG variant in this disease adds another evidence to the role of TFG in neurodegenerative disease.
UNASSIGNED: The finding of TFG variant of uncertain significance is a rare finding in amyotrophic lateral sclerosis. And with the identification of new TFG variant, it leads to further understanding of spectrum of TFG and its pathophysiology in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is the most common form of motor neuron disease. Mutations in TARDBP, the gene encoding the RNA-binding protein TDP-43, are responsible for about 5% of familial ALS. Here we report the clinical and biological features of an ALS patients with pA382T mutation in TPD-43 protein. Disease began with right hand muscles weakness, and equally involved upper and lower motor neuron with a classic phenotype, without cognitive impairment. While a family history of neurological diseases was reported, there was no evidence of familial frontotemporal dementia. Cultured fibroblasts from the patient were characterized by profound alterations of cell proteome, which impacts particularly the mitochondrial metabolic pathways and the endoplasmic reticulum. TDP-43 levels were similar to control, healthy fibroblasts, but a higher fraction localized in mitochondria. Mitochondrial network appeared fragmented, and the organelles smaller and more spheric. In agreement with impaired proteome and morphology of mitochondria, basal cell respiration was reduced. Mitochondrial DNA levels appeared normal. However, a higher amount of mitochondrial DNA was present in the cytosol, suggesting a pronounced mitochondrial DNA misplacement which can promote a pro-inflammatory response mediating by cGAS/STING. Thus, this case report further expands the clinical and pathological phenotype of A382T mutation.

To be, or not to be, that is the question. (William Shakespeare, Hamlet) Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2, respectively) play a role in trimming peptides that are too long to be bound and presented by class I HLA (HLA-I) molecules to CD8+ T cells. They may also affect the HLA-I-presented peptide repertoire by overtrimming potential epitopes. Both enzymes may also be released from the cell to cleave cytokine receptors and regulate blood pressure. Both enzymes are polymorphic, which affects their expression, specificity, and activity, resulting in their role in diseases associated with HLA-I. In this brief review, we concentrate on ERAP2, less investigated because of its lack in laboratory mice and 25% of humans, as well as a lower polymorphism. ERAP2 was found to be associated with several diseases and to influence ERAP1 effects. It was discovered recently that the defective ERAP2 gene, not encoding functional aminopeptidase, may nevertheless, during viral infections, produce a truncated protein isoform of unknown function, possibly interfering with ERAP1 and full-length ERAP2 by heterodimer formation. The disease associations of ERAP2, alone or in combination with ERAP1, are reviewed.

BACKGROUND: ACAT-related enzyme 2 required for viability 1 (ARV1) encodes a transmembrane lipid transporter of the endoplasmic reticulum, which is presented in all eukaryotes and in plants. Deficiency of ARV1 is clinically presented as autosomal recessive developmental and epileptic encephalopathy 38 (DEE38) in humans and in mice. So far, three different homozygous and two compound heterozygous ARV1 mutations in humans have been reported in 15 children.
METHODS: In this case report we present a novel homozygous in-frame ARV1-deletion (c.554_556delTAT, p.L185del) in a 21-year old Caucasian man with developmental delay, intellectual disability, seizures, walking and speech impairments, as well as with a dilated cardiomyopathy (DCM), which has not yet been firmly related to the ARV1-associated phenotype. Interestingly, this novel variant lies in the proximity of the p.G189R mutation, which was previously described in two brothers with DEE38 and dilated cardiomyopathy.
CONCLUSIONS: The finding of dilated cardiomyopathy in the presented as well as in three previously reported patients from two different families indicates that dilated cardiomyopathy is a part of the ARV1-induced DEE38 phenotype. However, more data are needed to make this conclusion definitive.

Biological networks are characterized by their connectivity and topology but also by their ability to transport materials. In the case of random transportation, the efficacy is measured by the time it takes to travel between two nodes of the network. We study here the consequences of a unidirectional transport mechanism occurring in the endoplasmic reticulum (ER) network, a structure present in the cell cytoplasm. This unidirectional transport mechanism is an active-waiting transportation, where molecules have to wait a random time before being transported from one node to the next one. We develop here a general theory of transport in an active network and find an unusual network transportation, where molecules group together in redundant packets instead of being disperse. Finally, the mean time to travel between two nodes of the ER is of the order of 20 min, but is reduced to 30 s when we consider the fastest particles because it uses optimal paths. To conclude, the present theory shows that unidirectional transport is an efficient and robust mechanism for fast molecular redistribution inside the ER.

BACKGROUND: It is clinically emergent to further understand the pathological mechanism to advance therapeutic strategy for endocrine tumors. A high amount of secretory protein with tumorigenic triggers are thought to induce unfolded protein response in endoplasmic reticulum in endocrine tumors, but its evidence is limited.
METHODS: A 40-year-old woman had an approximately 10-year history of intermittent headaches. After the incidental detection of a mass in her right adrenal gland by CT scan, she was admitted to our hospital. She had been diagnosed as type 1 Waardenburg syndrome with the symptoms of dystopia canthorum, blue iris, and left sensorineural hearing loss. Urinary catecholamine levels were markedly elevated. 123I-MIBG scintigraphy showed uptake in the mass in her adrenal gland. After the adrenalectomy, her headaches disappeared and urinary catecholamine levels decreased to normal range within 2 weeks. Genome sequencing revealed germline mutation of c.A175T (p.Ile59Phe) in transcription factor PAX3 gene and somatic novel mutation of c.1893_1898del (p. Asp631_Leu633delinsGlu) in proto-oncogene RET in her pheochromocytoma. RNA expression levels of RET were increased 139 times in her pheochromocytoma compared with her normal adrenal gland. Those of unfolded protein response markers, Bip/GRP78, CHOP, ATF4, and ATF6, were also increased in the pheochromocytoma.
CONCLUSIONS: We report a rare case of pheochromocytoma with type 1 Waardenburg syndrome. This is the first case to show the activation of unfolded protein response in the pheochromocytoma with the novel somatic mutation in RET gene. Our findings may support that unfolded protein response is activated in endocrine tumors, which potentially could be a candidate of therapeutic target.