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The sodium-phosphate co-transporter SLC34A2, and pulmonary alveolar microlithiasis: Presentation of an inbred family and a novel truncating mutation in exon 3.

ABSTRACT: Pulmonary alveolar microlithiasis is a disorder in which many tiny fragments (microliths) of calcium phosphate gradually accumulate in alveoli. Loss of function mutations in the gene SLC34A2 coding for the sodium phosphate co-transporter (NaPi-IIb) are responsible for genetic forms of alveolar microlithiasis. We now report a consanguineous Italian family from Calabria with two affected members segregating alveolar microlithiasis in a recessive fashion. We describe, for the first time, a novel loss of function mutation in the gene coding for NaPi-IIb. A careful description of the clinical phenotype is provided together with technical details for direct sequencing of the gene.

SUBMITTER: Vismara MF

PROVIDER: S-EPMC4681981 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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The sodium-phosphate co-transporter SLC34A2, and pulmonary alveolar microlithiasis: Presentation of an inbred family and a novel truncating mutation in exon 3.

Vismara Marco Favio Michele MF Colao Emma E Fabiani Fernanda F Bombardiere Francesco F Tamburrini Oscar O Alessio Caterina C Manti Francesco F Pelaia Gerolamo G Romeo Pasquale P Iuliano Rodolfo R Perrotti Nicola N

Respiratory medicine case reports 20150812

Pulmonary alveolar microlithiasis is a disorder in which many tiny fragments (microliths) of calcium phosphate gradually accumulate in alveoli. Loss of function mutations in the gene SLC34A2 coding for the sodium phosphate co-transporter (NaPi-IIb) are responsible for genetic forms of alveolar microlithiasis. We now report a consanguineous Italian family from Calabria with two affected members segregating alveolar microlithiasis in a recessive fashion. We describe, for the first time, a novel lo ...[more]

PMID: 26744662

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Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis.

Project description:Pulmonary alveolar microlithiasis (PAM) is a rare disease characterized by the deposition of calcium phosphate microliths throughout the lungs. We first identified a PAM locus by homozygosity mapping to 4p15, then identified, by a candidate-gene approach, the gene responsible for the disease as SLC34A2 (the type IIb sodium-phosphate cotransporter gene), which is involved in phosphate homeostasis in several organs. We identified six homozygous exonic mutations in the seven unrelated patients with PAM we studied. Three of the mutations were frameshifts, one was a chain termination, one was an amino acid substitution, and one was a deletion spanning the minimal promoter and the first exon. Absence of functional protein product of the gene is compatible with calcium phosphate deposition in alveolar airspaces. We show that impaired activity of the phosphate transporter is presumably responsible for the microliths and that PAM is a recessive monogenic disease with full penetrance. Testicular microlithiasis (TM) is a disease that is more common than PAM. It is often associated with cancer and infertility. Since the gene we identified is also expressed in testis, we searched for mutations in subjects with TM. In 2 of the 15 subjects with TM we studied, we identified two rare variants, one synonymous and the other noncoding, that are possibly associated with the condition.

| S-EPMC1592565 | biostudies-literature

A novel SLC34A2 mutation in a patient with pulmonary alveolar microlithiasis.

Project description:Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive disease caused by mutations in SLC34A2 and characterized by intra-alveolar accumulation of microliths. We diagnosed a case of PAM in a 27-year-old Japanese female and identified a novel mutation in SLC34A2 (c.1390 G>C [G464R] in exon 12).

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A case of pulmonary alveolar microlithiasis associated with a homozygous 195 kb deletion encompassing the entire SLC34A2 gene.

Project description:With around 500 cases published worldwide, pulmonary alveolar microlithiasis is a rare disorder with an autosomal recessive pattern of inheritance. We show for the first time that homozygous deletions encompassing the entire SCL34A2 can be associated with this rare genetic pulmonary disease.

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SLC34A2 gene compound heterozygous mutation identification in a patient with pulmonary alveolar microlithiasis and computational 3D protein structure prediction.

Project description:We recently diagnosed a patient with pulmonary alveolar microlithiasis (PAM). Because loss-of-function mutations of the SLC34A2 gene are responsible for the development of PAM, we sought to sequence the SLC34A2 gene of the patient and his direct relatives, with a purpose to identify mutations that caused the PAM of the patient as well as the carriers of his family. We found a novel compound heterozygous mutation of the SLC34A2 gene in this patient, which were the mutations of c.1363T > C (p. Y455H) in exon 12 and c.910A > T (p. K304X) in exon 8. Computational prediction of three-dimensional (3D) structures of the mutants revealed that the Y455H mutation resulted in a formation of irregular coils in the trans-membrane domain and the K304X mutation resulted in protein truncation. Our study suggested that sequencing of the SLC34A2 gene together with a computational prediction of the 3D structures of the mutated proteins may be useful in PAM diagnosis and prognosis.

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Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment.

Project description:Pulmonary alveolar microlithiasis (PAM) is a rare, autosomal recessive lung disorder associated with progressive accumulation of calcium phosphate microliths. Inactivating mutations in SLC34A2, which encodes the NPT2b sodium-dependent phosphate cotransporter, has been proposed as a cause of PAM. We show that epithelial deletion of Npt2b in mice results in a progressive pulmonary process characterized by diffuse alveolar microlith accumulation, radiographic opacification, restrictive physiology, inflammation, fibrosis, and an unexpected alveolar phospholipidosis. Cytokine and surfactant protein elevations in the alveolar lavage and serum of PAM mice and confirmed in serum from PAM patients identify serum MCP-1 (monocyte chemotactic protein 1) and SP-D (surfactant protein D) as potential biomarkers. Microliths introduced by adoptive transfer into the lungs of wild-type mice produce marked macrophage-rich inflammation and elevation of serum MCP-1 that peaks at 1 week and resolves at 1 month, concomitant with clearance of stones. Microliths isolated by bronchoalveolar lavage readily dissolve in EDTA, and therapeutic whole-lung EDTA lavage reduces the burden of stones in the lungs. A low-phosphate diet prevents microlith formation in young animals and reduces lung injury on the basis of reduction in serum SP-D. The burden of pulmonary calcium deposits in established PAM is also diminished within 4 weeks by a low-phosphate diet challenge. These data support a causative role for Npt2b in the pathogenesis of PAM and the use of the PAM mouse model as a preclinical platform for the development of biomarkers and therapeutic strategies.

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The intestinal phosphate transporter NaPi-IIb (Slc34a2) is required to protect bone during dietary phosphate restriction.

Project description:NaPi-IIb/Slc34a2 is a Na+-dependent phosphate transporter that accounts for the majority of active phosphate transport into intestinal epithelial cells. Its abundance is regulated by dietary phosphate, being high during dietary phosphate restriction. Intestinal ablation of NaPi-IIb in mice leads to increased fecal excretion of phosphate, which is compensated by enhanced renal reabsorption. Here we compared the adaptation to dietary phosphate of wild type (WT) and NaPi-IIb-/- mice. High phosphate diet (HPD) increased fecal and urinary excretion of phosphate in both groups, though NaPi-IIb-/- mice still showed lower urinary excretion than WT. In both genotypes low dietary phosphate (LDP) resulted in reduced fecal excretion and almost undetectable urinary excretion of phosphate. Consistently, the expression of renal cotransporters after prolonged LDP was similar in both groups. Plasma phosphate declined more rapidly in NaPi-IIb-/- mice upon LDP, though both genotypes had comparable levels of 1,25(OH)2vitamin D3, parathyroid hormone and fibroblast growth factor 23. Instead, NaPi-IIb-/- mice fed LDP had exacerbated hypercalciuria, higher urinary excretion of corticosterone and deoxypyridinoline, lower bone mineral density and higher number of osteoclasts. These data suggest that during dietary phosphate restriction NaPi-IIb-mediated intestinal absorption prevents excessive demineralization of bone as an alternative source of phosphate.

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Pulmonary alveolar microlithiasis: no longer in the stone age.

Project description:Pulmonary alveolar microlithiasis (PAM) is a rare parenchymal lung disease caused by variants in the SCL34A2 gene and characterised by the accumulation of intra-alveolar microliths. PAM has been reported in fewer than 1100 cases throughout the world. It is an autosomal recessive hereditary disease and often associated with consanguinity. Progress with respect to the genetic background and pathophysiology has resulted in an increased understanding of the disease in recent years. Until now, 30 genetic different SLC34A2 variants have been reported, which all are considered significant for disease development. There is no sex difference and the majority of cases are diagnosed at the age of 30-40?years. Many patients are asymptomatic and the diagnosis is made at random. When symptomatic, dyspnoea, cough, chest pain and fatigue are common complaints. The diagnosis of PAM can confidently be based on typical radiographic findings and genetic testing proving rare biallelic SCL34A2 gene variants. Bronchoalveolar lavage and histopathology may show microliths. There is no disease-specific treatment and management is supportive. Lung transplantation should be considered in advanced cases.

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Pulmonary alveolar microlithiasis: A report of two unique cases.

Project description:Pulmonary alveolar microlithiasis (PAM) is an inherited autosomal recessive disease. PAM is classically characterized by calcium phosphate deposition within alveolar airspaces due to SLC34A2 (solute carrier family 34 member 2) gene mutation located on chromosome 4p15.2. Such cellular genetic mutation would lead to a defect in the sodium-phosphate transporter channel located in alveolar epithelial cells type-II. Ultimately, it would result in a malfunction of alveolar epithelial cells and the failure of these cells to clear-up the released phosphorous particles in the cellular surfactant recycling. PAM is usually diagnosed in adulthood, frequently notable in the third and fourth decades of life, occasionally can be associated with more severe clinical presentation and radiological findings. Nevertheless, the disease could manifest itself in the pediatric age group, which either shows non-specific signs and symptoms or be exclusively asymptomatic. Histopathological examination is the gold standard for the PAM diagnosis. Genetic counseling and testing might benefit the patient's family members. Herein, we present 2 cases of PAM in the pediatric age group, along with their clinical history, presentation, radiological studies, and histopathology findings, as well as a brief literature review.

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Novel insights into pulmonary phosphate homeostasis and osteoclastogenesis emerge from the study of pulmonary alveolar microlithiasis.

Project description:Pulmonary alveolar microlithiasis (PAM) is an autosomal recessive lung disease caused by a deficiency in the pulmonary epithelial Npt2b sodium-phosphate co-transporter that results in accumulation of phosphate and formation of hydroxyapatite microliths in the alveolar space. The single cell transcriptomic analysis of a PAM lung explant showing a robust osteoclast gene signature in alveolar monocytes and the finding that calcium phosphate microliths contain a rich protein and lipid matrix that includes bone resorbing osteoclast enzymes suggested a role for osteoclast-like cells in the defense against microliths.

2022-09-26 | GSE199329 | GEO

Microlithiasis of Seminal Vesicles and Severe Oligoasthenospermia in Pulmonary Alveolar Microlithiasis (PAM): Report of An Unusual Sporadic Case.

Project description:Pulmonary alveolar microlithiasis (PAM) is classified as an elective dysmetabolic thesaurotic pneumoalveolitis and characterized by the presence within the alveoli of the lungs of myriad of tiny calculi. The classic presentation of the chest radiography is unmistakable with multiple small "sand-like" opacities diffusely involving both lung fields. We present a case of male infertility for hypoposia and severe oligoasthenospermia in a young patient with recurrent haematuria and small calcifications in the seminal vesicles similar to pulmonary microliths. PAM was diagnosed on routine chest radiography, com- puter tomography (CT), transbronchial biopsy and bronchoalveolar lavage (BAL).

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