Impaired phosphate transport in SLC34A2 variants in patients with pulmonary alveolar microlithiasis.

BACKGROUND: Variants in SLC34A2 encoding the sodium-dependent phosphate transport protein 2b (NaPi-IIb) cause the rare lung disease pulmonary alveolar microlithiasis (PAM). PAM is characterised by the deposition of calcium-phosphate concretions in the alveoli usually progressing over time. No effective treatment is available. So far, 30 allelic variants in patients have been reported but only a few have been functionally characterised. This study aimed to determine the impact of selected SLC34A2 variants on transporter expression and phosphate uptake in cellular studies. METHODS: Two nonsense variants (c.910A > T and c.1456C > T), one frameshift (c.1328delT), and one in-frame deletion (c.1402_1404delACC) previously reported in patients with PAM were selected for investigation. Wild-type and mutant c-Myc-tagged human NaPi-IIb constructs were expressed in Xenopus laevis oocytes. The transport function was investigated with a 32Pi uptake assay. NaPi-IIb protein expression and localisation were determined with immunoblotting and immunohistochemistry, respectively. RESULTS: Oocytes injected with the wild-type human NaPi-IIb construct had significant 32Pi transport compared to water-injected oocytes. In addition, the protein had a molecular weight as expected for the glycosylated form, and it was readily detectable in the oocyte membrane. Although the protein from the Thr468del construct was synthesised and expressed in the oocyte membrane, phosphate transport was similar to non-injected control oocytes. All other mutants were non-functional and not expressed in the membrane, consistent with the expected impact of the truncations caused by premature stop codons. CONCLUSIONS: Of four analysed SLC34A2 variants, only the Thr468del showed similar protein expression as the wild-type cotransporter in the oocyte membrane. All mutant transporters were non-functional, supporting that dysfunction of NaPi-IIb underlies the pathology of PAM.

Circular RNA F-circSR derived from SLC34A2-ROS1 fusion gene promotes cell migration in non-small cell lung cancer.

Cancer-associated chromosomal translocations are reported to generate oncogenic circular RNA (circRNA), contributing to tumorigenesis. The fusion gene SLC34A2-ROS1 (solute carrier family 34 member 2 and ROS proto-oncogene 1) plays an important role in non-small cell lung cancer (NSCLC) progression. However, whether SLC34A2-ROS1 gene can produce circRNA remains unknown. Here, we identified two novel circRNAs (F-circSR1 and F-circSR2) generated from SLC34A2-ROS1 fusion gene, while F-circSR1 has higher expression than F-circSR2. Functional studies through gain- and loss-of-function strategies showed that both F-circSRs promote cell migration in lung cancer cells, whereas they have little effect on cell proliferation. Using the minigene GFP reporter assay, we verified that the flanking complementary sequences with canonical splicing sites are essential for F-circSR biogenesis. Therefore, our findings demonstrate the oncogenic role of F-circSR in NSCLC and highlight its therapeutic potential.

SLC34A2 regulates miR-25-Gsk3ß signaling pathway to affect tumor progression in gastric cancer stem cell-like cells.

A novel paradigm in tumor biology suggests that gastric cancer progression is driven by gastric cancer stem cell-like cells (GCSCs), but molecular mechanisms regulating tumorigenic and self-renewal potential of GCSCs are still unclear. Here, we aim to investigate biological function of SLC34A2 in regulating sphere formation and tumorigenicity (both are the hallmark of CSCs) of GCSCs and its underlying mechanisms. Our findings testified that CD44+ cells which were derived from fresh primary gastric cancer samples and cell lines displayed stem cell-like features. Significantly, SLC34A2 is increased in CD44+ GCSCs compared with those in adherent counterpart from CD44+ GCSCs. On clinic, SLC34A2 is overexpressed in primary tumor tissues compared with adjacent counterparts. We showed that SLC34A2 regulated sphere formation and self-renewal properties of CD44+ GCSCs in vitro and in vivo. Mechanistic investigations revealed that Gsk3ß was the most strikingly up-regulated gene in response to SLC34A2 knockdown in GCSCs and Wnt/ß-cantenin signaling was required for SLC34A2-mediated sphere formation. Furthermore, SLC34A2 directly binds specific sites in the miR-25 promoter region and that the promoter activity is decreased after the mutation of putative SLC34A2-binding sites, indicating that SLC34A2 is required for the transcriptional induction of miR-25. Meanwhile, luciferase assays showed that miR-25 directly targeted Gsk3ß in CD44+ GCSCs. Overall, our findings define a SLC34A2-miR-25-Gsk3ß pathway in the regulation of GCSCs features and gastric cancer progression, with potential therapeutic applications in blocking their progression.

Identification of a mammalian silicon transporter.

Silicon (Si) has long been known to play a major physiological and structural role in certain organisms, including diatoms, sponges, and many higher plants, leading to the recent identification of multiple proteins responsible for Si transport in a range of algal and plant species. In mammals, despite several convincing studies suggesting that silicon is an important factor in bone development and connective tissue health, there is a critical lack of understanding about the biochemical pathways that enable Si homeostasis. Here we report the identification of a mammalian efflux Si transporter, namely Slc34a2 (also termed NaPiIIb), a known sodium-phosphate cotransporter, which was upregulated in rat kidney following chronic dietary Si deprivation. Normal rat renal epithelium demonstrated punctate expression of Slc34a2, and when the protein was heterologously expressed in Xenopus laevis oocytes, Si efflux activity (i.e., movement of Si out of cells) was induced and was quantitatively similar to that induced by the known plant Si transporter OsLsi2 in the same expression system. Interestingly, Si efflux appeared saturable over time, but it did not vary as a function of extracellular [Formula: see text] or Na+ concentration, suggesting that Slc34a2 harbors a functionally independent transport site for Si operating in the reverse direction to the site for phosphate. Indeed, in rats with dietary Si depletion-induced upregulation of transporter expression, there was increased urinary phosphate excretion. This is the first evidence of an active Si transport protein in mammals and points towards an important role for Si in vertebrates and explains interactions between dietary phosphate and silicon.

Decreased expression of miR-939 contributes to chemoresistance and metastasis of gastric cancer via dysregulation of SLC34A2 and Raf/MEK/ERK pathway.

BACKGROUND: The development of chemoresistance and metastasis are the leading causes of death for gastric cancer (GC) patients, however, the molecular mechanisms involved remain unclear. Dysregulation of miRNAs is associated with a variety of disease, including GC. Recently, microarray profiling analysis revealed that miR-939 was dysregulated in human GC samples, but the role of miR-939 in GC has not been intensively investigated. METHODS: In the present study, we firstly examined the expression pattern of miR-939 in two independent cohorts of clinical GC samples: one cohort of 112 GC patients with stage I-III disease who underwent surgery followed by adjuvant chemotherapy; and another cohort of 110 GC patients with stage IV disease who received palliative chemotherapy. A series of in vivo and in vitro assays were then performed to investigate the function of miR-939 in GC. RESULTS: We detected that reduced expression of miR-939 was associated with chemoresistance and increased risk of tumor recurrence in GC patients. Further function study demonstrated that overexpression of miR-939 suppressed GC cell growth, and enhanced 5-fluorouracil-induced chemosensitivity by compromising cellular growth and inducing apoptosis in vitro and in vivo. Moreover, miR-939 repressed the migration and invasion of GC cells in vitro, and diminished the occurrence of lung metastasis in vivo. We further identified solute carrier family 34 member 2 (SLC34A2) was a novel target of miR-939. Mechanistically, we elucidated that miR-939 exerted its function mainly through inhibiting SLC34A2/Raf/MEK/ERK pathway, which is activated in GC. Multivariate analysis identified miR-939, SLC34A2, and their combination as independent indicators for poor prognosis and tumor recurrence in GC patients. CONCLUSION: Our data indicate that miR-939 acts as a tumor suppressor miRNA in GC, and miR-939/SLC34A2 axis represents a novel therapeutic strategy for future GC treatment.

Intrinsic gene changes determine the successful establishment of stable renal cancer cell lines from tumor tissue.

Human tumor cell lines, especially those with complete data and follow-up, are important tools in tumor biological studies. Clear cell renal cell cancer (ccRCC) is not sensitive to radiotherapy or chemotherapy, and treatment of patients with distant metastasis relies on targeted therapy. Here, we report the establishment of seven new ccRCC stable cell lines that were continuously cultured for more than 20 generations among 81 cases of renal cell cancer. Moreover, gene expression and methylation in the established cell lines, in those that had a finite in vitro life span of less than 10 generations, and in cells that originated from the same culture at different generations were profiled using microarrays. Genes including SLC34A2, SEPP1, SULT1C4 and others were differentially expressed in established cell lines and finite cell lines, and changes in their expression might be caused by methylation or demethylation. The expression level of SLC34A2 was related not only to the life span in vitro culture but also to tumor size. Additionally, six of the seven new ccRCC cell lines had VHL deletions or termination mutations. So in addition to the establishment of seven new ccRCC cell lines with complete clinical data, we conclude that genes such as SLC34A2 and VHL play key roles in the continuous in vitro growth and development of ccRCC.

High expression of SLC34A2 is a favorable prognostic marker in lung adenocarcinoma patients.

Dysregulation of SLC34A2 (NaPi2b) in tumors has attracted wide attention, but its expression and function in non-small cell lung cancer remains unclear. By examining its expression in lung adenocarcinoma and correlation to patient outcome, we aimed to explore its prognostic and therapeutic values in this deadly disease. Overall, 175 cases of lung adenocarcinoma sample were included in this study. Histological subtyping of them was diagnosed according to standards of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society in 2011. Protein expression of SLC34A2 and anaplastic lymphoma kinase in these samples was determined by immunohistochemistry. Epidermal growth factor receptor mutations were examined using amplification refractory mutation system. Statistical analysis was performed using software of Pearson's correlation coefficient. High expression of SLC34A2 was identified in about 2/3 patients and correlated with significantly better patient's overall survival. Epidermal growth factor receptor mutations were detected in about 53% of patients with no statistically significant difference to patient's overall survival. Anaplastic lymphoma kinase rearrangement was found in 8 out of 175 patients, harboring this abnormality leads to shorter overall survival. No correlation has been found between SLC34A2 expression and epidermal growth factor receptor mutation or anaplastic lymphoma kinase rearrangements in lung adenocarcinoma. High expression of SLC34A2 is present in about 3/4 lung adenocarcinoma samples and predicts better outcome. Since it is a membrane protein, antibody-based drugs targeting this marker might bring new resolution to this deadly disease.

The effects and mechanisms of SLC34A2 on maintaining stem cell-like phenotypes in CD147+ breast cancer stem cells.

The cancer stem cell (CSC) hypothesis has gained significant recognition in describing tumorigenesis. Identification of the factors critical to development of breast cancer stem cells (BCSCs) may provide insight into the improvement of effective therapies against breast cancer. In this study, we aim to investigate the biological function of SLC34A2 in affecting the stem cell-like phenotypes in BCSCs and its underlying mechanisms. We demonstrated that CD147+ cells from breast cancer tissue samples and cell lines possessed BCSC-like features, including the ability of self-renewal in vitro, differentiation, and tumorigenic potential in vivo. Flow cytometry analysis showed the presence of a variable fraction of CD147+ cells in 9 of 10 tumor samples. Significantly, SLC34A2 expression in CD147+ BCSCs was enhanced compared with that in differentiated adherent progeny of CD147+ BCSCs and adherently cultured cell line cells. In breast cancer patient cohorts, SLC34A2 expression was found increased in 9 of 10 tumor samples. By using lentiviral-based approach, si-SLC34A2-transduced CD147+ BCSCs showed decreased ability of sphere formation, cell viability in vitro, and tumorigenicity in vivo, which suggested the essential role of SLC34A2 in CD147+ BCSCs. Furthermore, PI3K/AKT pathway and SOX2 were found necessary to maintain the stemness of CD147+ BCSCs by using LY294002 or lentiviral-si-SOX2. Finally, we indicated that SLC34A2 could regulate SOX2 to maintain the stem cell-like features in CD147+ BCSCs through PI3K/AKT pathway. Therefore, our report identifies a novel role of SLC34A2 in BCSCs' state regulation and establishes a rationale for targeting the SLC34A2/PI3K/AKT/SOX2 signaling pathway for breast cancer therapy.

Characterization of the isoforms of type IIb sodium-dependent phosphate cotransporter (Slc34a2) in yellow catfish, Pelteobagrus fulvidraco, and their vitamin D3-regulated expression under low-phosphate conditions.

In this study, two isoforms slc34a2 genes (type IIb sodium-dependent phosphate cotransporter), slc34a2a2 and slc34a2b, were cloned from intestine and kidney of yellow catfish (Pelteobagrus fulvidraco), with rapid amplification of cDNA ends. The structure differences and the regulation effects of dietary VD3 under low phosphorus were compared among three isoforms of slc34a2 in yellow catfish. The predicted Slc34a2a2 and Slc34a2b proteins match 65 % and 53.8 % sequence identity, with Slc34a2a1, respectively. The membrane-spanning domains were different among these three isoforms. Intestinal Slc34a2a1 and Slc34a2a2 proteins had eight and eleven transmembrane domains, while renal Slc34a2b protein had nine. The tissue distribution study showed that same as slc34a2a1, slc34a2a2 mRNA was mainly distributed in intestine and slc34a2b mRNA in kidney. The effect of vitamin D3 (VD3) level on slc34a2 subfamily expression under low-phosphate conditions, induced by the addition of 0 (VD0), 324 (VD1), 1243 (VD2), 3621 (VD3), 8040 (VD4), or 22700 (VD5) IU VD3/kg feed, was assessed by qPCR. The dose-responsive expression of intestinal slc34a2a2 and high expression of intestinal slc34a2a2 in VD5 together with peak expression of kidney slc34a2b in VD3 coincided with the accumulation of body phosphate content. These data suggested that appropriate level of dietary VD3 up-regulated slc34a2a1, slc34a2a2, and slc34a2b mRNA levels, which increased phosphate retention. In conclusion, the current study provided another possible approach to improve dietary phosphate utilization by adding appropriate level of VD3 to a low-phosphate diet to regulate intestinal and renal slc34a2 gene expression and thus minimize the excretion of phosphorus in yellow catfish.

Enhanced SLC34A2 in breast cancer stem cell-like cells induces chemotherapeutic resistance to doxorubicin via SLC34A2-Bmi1-ABCC5 signaling.

Even though early detection methods and treatment options are greatly improved, chemoresistance is still a tremendous challenge for breast cancer therapy. Breast cancer stem cells (BCSCs) represent a subpopulation that is central to chemoresistance. We aim to investigate the relationship between SLC34A2 and chemoresistance in BCSCs and identify the underlying mechanisms by which SLC34A2 regulates chemoresistance in BCSCs. Fluorescence Activated Cell Sorting (FACS) analysis showed the presence of a variable fraction of CD44(+)CD24(-) cells in 25 out of 25 breast cancer samples. We cultured primary breast cancer sample cells and breast cancer cell line cells to induce sphere formation in serum-free medium. Following sorting of CD44(+)CD24(-) cells from spheres, we showed that CD44(+)CD24(-) cells displayed stem cell-like features and were resistant to chemotherapy drug doxorubicin. Significantly, enhanced SLC34A2 expression correlated with chemoresponse and survival of breast cancer patients. We subsequently indicated that increased SLC34A2 expression in BCSCs directly contributed to their chemoresistance by a series of in vitro and in vivo experiments. Furthermore, we demonstrated that SLC34A2 induced chemoresistance in BCSCs via SLC34A2-Bmi1-ABCC5 signaling. Finally, we showed that ABCC5 was a direct transcriptional target of Bmi1 by chromatin immunoprecipitation (ChIP). In conclusion, our work indicated that decreased SLC34A2 expression sensitized BCSCs to doxorubicin via SLC34A2-Bmi1-ABCC5 signaling and shed new light on understanding the mechanism of chemoresistance in BCSCs. This study not only bridges the missing link between stem cell-related transcription factor (Bmi1) and ABC transporter (ABCC5) but also contributes to development of potential therapeutics against breast cancer.

The effects and mechanisms of SLC34A2 on tumorigenicity in human non-small cell lung cancer stem cells.

A novel paradigm in tumor biology suggests that non-small cell lung cancer (NSCLC) growth is driven by lung cancer stem cell-like cells (LCSCs), but molecular mechanisms regulating tumorigenic and self-renewal potential of LCSCs are still unclear. Here, we aim to investigate biological function of SLC34A2 in regulating tumorigenicity of LCSCs and its underlying mechanisms. Our findings testified that CD166(+) cells which were derived from fresh primary NSCLC samples displayed stem cell-like features. Fluorescence-activated cell sorting (FACS) analysis showed the presence of a variable fraction of CD166 cells in 15 out of 15 NSCLC samples. Significantly, CD166(+) LCSCs from primary NSCLC tumors expressed high level of SLC34A2 which was required for CD166(+) LCSCs tumorigenic and self-renewal potential. In NSCLC patient cohort, increased SLC34A2 expression correlated with histology, which suggests a potential role of SLC34A2 in CD166(+) LCSCs. Furthermore, Wnt/ß-catenin pathway and Bmi1 were found necessary for tumorigenicity and self-renewal capacity of CD166(+) LCSCs by a series in vitro and in vivo experiments. Then, our study indicated that SLC34A2 regulated Bmi1 to promote tumorigenic and self-renewal potential of CD166(+) LCSCs through Wnt/ß-catenin pathway. In this study, the characterization of molecular basis of SLC34A2 in CD166(+) LCSCs not only allows for better understanding of the mechanisms regulating tumorigenicity of this specific population of NSCLC cells but also provides insight into the gradual improvement of more effective cancer therapies against this disease.

Characterizing and evaluating the expression of the type IIb sodium-dependent phosphate cotransporter (slc34a2) gene and its potential influence on phosphorus utilization efficiency in yellow catfish (Pelteobagrus fulvidraco).

A sodium-dependent phosphate cotransporter gene, NaPi-IIb (slc34a2), was isolated from yellow catfish (Pelteobagrus fulvidraco) intestine through homology cloning and the rapid amplification of cDNA ends. The full-length cDNA of slc34a2 consisted of 2326 bp with an open reading frame encoding 621 amino acids, a 160-bp 5' untranslated region, and a 300-bp 3' untranslated region. The deduced amino acid sequence showed 79.0 and 70.9% sequence identity to Astyanax mexicanus and Pundamilia nyererei, respectively. The membrane-spanning domains based on the hydrophilic and hydrophobic properties of the deduced amino acids were predicted, and results showed that the putative protein had eight transmembrane domains, with the intracellular NH2 and COOH termini. Two functional regions including first intracellular loop and third extracellular loop as well as the six N-glycosylation sites in second extracellular loop were found. The slc34a2 mRNA in the tested tissues was examined through semiquantitative reverse transcription polymerase chain reaction and quantitative real-time PCR, with the highest level found in the anterior intestine, followed by the posterior and middle intestines. The slc34a2 mRNA expression in the whole intestine under different dietary phosphorus (P) treatments was detected using qPCR. The results showed that the slc34a2 expression levels in the low-P groups (0.33 and 0.56%) were significantly higher (p < 0.05) than levels in the sufficient-P (0.81%) and high-P (1.15, 1.31, and 1.57%) groups. High expression of slc34a2 mRNA in low-P groups stimulated P utilization efficiency, indicating the close relationship between genotype and phenotype in yellow catfish. In contrast with conventional strategies (formula and feeding strategies), this study provided another possible approach by using molecular techniques to increase the P utilization in yellow catfish.

SLC34A2 Targets in Calcium/Phosphorus Homeostasis of Mammary Gland and Involvement in Development of Clinical Mastitis in Dairy Cows.

The type II Na/Pi co-transporter (NaPi2b), encoded by the solute carrier (SLC) transporter 34A2 (SLC34A2), is responsible for calcium (Ca) and phosphorus (P) homeostasis. Unbalanced Ca/P metabolism induces mastitis in dairy cows. However, the specific role of SLC34A2 in regulating this imbalance in Holstein cows with clinical mastitis (CM) remains unclear. The aim of this study was to investigate the role of SLC34A2 and identify differentially expressed proteins (DEPs) that interact with SLC34A2 and are associated with Ca/P metabolism in dairy cows with CM. Immunohistochemical and immunofluorescence staining results showed that SLC34A2 was located primarily in the mammary epithelial cells of the mammary alveoli in both the control (healthy cows, Con/C) and CM groups. Compared to the Con/C group, the relative expression of the SLC34A2 gene and protein were significantly downregulated in the CM group. We identified 12 important DEPs included in 11 GO terms and two pathways interacting with SLC34A2 using data-independent acquisition proteomics. The PPI (protein-and-protein interaction) network results suggested that these DEPs were associated with ion metabolism and homeostasis, especially SLC34A2. These results demonstrate that SLC34A2 downregulation is negatively correlated with the occurrence and development of CM in Holstein cows, providing a basis for exploring the function and regulatory mechanism of SLC34A2 in Ca/P metabolism and homeostasis in Holstein cows with CM.

SLC34A2 promotes cell proliferation by activating STX17-mediated autophagy in esophageal squamous cell carcinoma.

BACKGROUND: Solute carrier family 34 member 2 (SLC34A2) has been implicated in the development of various malignancies. However, the clinical significance and underlying molecular mechanisms of SLC34A2 in esophageal squamous cell carcinoma (ESCC) remain elusive. METHODS: Western blotting, quantitative real-time PCR and immunohistochemistry were utilized to evaluate the expression levels of SLC34A2 mRNA/protein in ESCC cell lines or tissues. Kaplan-Meier curves were employed for survival analysis. CCK-8, colony formation, EdU and xenograft tumor model assays were conducted to determine the impact of SLC34A2 on ESCC cell proliferation. Cell cycle was examined using flow cytometry. RNA-sequencing and enrichment analysis were carried out to explore the potential signaling pathways. The autophagic flux was evaluated by western blotting, mRFP-GFP-LC3 reporter system and transmission electron microscopy. Immunoprecipitation and mass spectrometry were utilized for identification of potential SLC34A2-interacting proteins. Cycloheximide (CHX) chase and ubiquitination assays were conducted to test the protein stability. RESULTS: The expression of SLC34A2 was significantly upregulated in ESCC and correlated with unfavorable clinicopathologic characteristics particularly the Ki-67 labeling index and poor prognosis of ESCC patients. Overexpression of SLC34A2 promoted ESCC cell proliferation, while silencing SLC34A2 had the opposite effect. Moreover, SLC34A2 induced autophagy to promote ESCC cell proliferation, whereas inhibition of autophagy suppressed the proliferation of ESCC cells. Further studies showed that SLC34A2 interacted with an autophagy-related protein STX17 to promote autophagy and proliferation of ESCC cells by inhibiting the ubiquitination and degradation of STX17. CONCLUSIONS: These findings indicate that SLC34A2 may serve as a prognostic biomarker for ESCC.

Alveolar Microlithiasis with Mild Clinical Symptoms But Severe Imaging Findings: A Case Report.

Pulmonary alveolar microlithiasis (PAM) is a rare genetic disorder that causes calcium phosphate microliths to form in the alveoli. Symptoms usually appear in a person's third or fourth decade of life. A definitive diagnosis does not always demand a lung biopsy but can be achieved in families with more than one member with PAM and compatible chest imaging. We present the case of a 47-year-old woman referred to us for shortness of breath. Chest imaging revealed bilateral diffuse ground-glass opacities, interlobar fissure calcification, and subpleural linear calcifications, leading to a diagnosis of PAM. Although there is no specific treatment for this condition, early diagnosis can help prevent it from progressing rapidly by avoiding exposure to risk factors.

Severe pulmonary hypertension in pulmonary alveolar microlithiasis: A comprehensive literature review.

This review focuses on Pulmonary Alveolar Microlithiasis (PAM), an autosomal recessive genetic disorder characterized by calcium crystal deposits (microliths) resulting from loss of function of the SLC34A2 gene. PAM is a rare disease with approximately 1100 reported cases globally. The historical context of its discovery and the genetic, epidemiological, and pathophysiological aspects are discussed. PAM falls under interstitial lung diseases and is associated with pulmonary hypertension (PH), primarily categorized as Group 3 PH. The clinical manifestations, diagnostic approaches, and challenging aspects of treatment are explored. A clinical case of PAM with severe pulmonary hypertension is presented, emphasizing the importance of comprehensive evaluation and the potential benefits of phosphodiesterase-5 inhibitors (PDE5i) therapy. Despite limited therapeutic options and challenging diagnosis, this review sheds light on recent developments and emerging treatments for PAM and associated pulmonary hypertension.

Pulmonary Alveolar Microlithiasis in a Middle-Aged Man Presenting With Respiratory Failure: A Case Report and Review of the Literature.

Pulmonary alveolar microlithiasis (PAM) is an autosomal recessive disease of the lung, characterized by diffuse deposits of intra-alveolar calcium phosphate microliths. It usually affects both sexes, presenting mostly in the second and third decades. The clinical course is highly variable, ranging from being asymptomatic to respiratory failure. PAM is usually diagnosed after careful clinical, radiological, and pathological evaluation, usually when patients present for other medical purposes. Here, a case of PAM in a middle-aged man presenting with acute-on-chronic hypoxemic respiratory failure is reported, with a review of the literature.

Pulmonary alveolar microlithiasis: a rare case report from Syria.

Introduction and importance: This report presents a case of pulmonary alveolar microlithiasis (PAM), a rare disease characterized by dry cough, dyspnea, and chest pain. Most reported cases are from Turkey, with a frequency of 1.85 in 1 million, and there are no documented cases from Syria in the medical literature. Here, we present the first case report from Syria. Case presentation: A 56-year-old male patient complained of a dry cough that began 4 years ago and had worsened over the last 3 months, along with a grade I dyspnea. Chest radiograph showed a 'sandstorm-like' appearance, and a computed tomography scan revealed diffuse ground-glass opacities. To confirm the diagnosis, we performed a transbronchial lung biopsy and bronchial washing. Histopathology results revealed interalveolar calcification consistent with PAM. The diagnosis was based on radiological and lung biopsy findings. The patient received oxygen therapy, resulting in significant improvement. We recommended the use of a home oxygen machine for episodes of shortness of breath. Clinical discussion: PAM is an autosomal recessive disease caused by a mutation in the SLC34A2 gene (solute carrier family 34, member 2 gene), characterized by intra-alveolar airspace microliths called calcospherites. Miliary tuberculosis should be considered a differential diagnosis. Conclusions: The disease progresses slowly and is often diagnosed incidentally. Lung transplantation remains the only effective treatment.