A case of pulmonary alveolar microlithiasis with an intragenetic deletion in SLC34A2 detected by a genome-wide SNP study

Abstract

A case of pulmonary alveolar microlithiasis occurring in an inbred family is presented. A genome-wide analysis of the patient's genomic DNA using a high-density single nucleotide polymorphism (SNP) array revealed a small intragenetic mutation at SLC34A2. The results suggest that the high-density SNP array has the power to identify a recessive disease gene(s) even in the analysis of only a single inbred patient.Inbreeding increases the chance for a mutant gene to become homozygous in the offspring and thus for autosomal recessive diseases to develop.1 The increased homozygosity is attributed to the appearance of chromosomal regions called autosomal segments, 2 where both strands of homologous chromosomes are identical by descent (ie, derived from a single chromosome of a single ancestor). In inbred children affected by an autosomal recessive disease, the causative gene is very likely to be in the autozygous segments. Recent high-density single nucleotide polymorphism (SNP) arrays are able to determine both of the SNP genotypes genome-wide and the copy number of each chromosomal location. A patient with pulmonary alveolar microlithiasis was investigated using the array which revealed a small intragenetic deletion in the SLC34A2 gene, the gene considered to be the cause of the disease. CASE REPORTA 56-year-old woman was admitted to hospital with progressive dyspnoea, severe systemic oedema and a weight increase from 45 kg to 60 kg. She had been notified for the first time in her 30s that her chest radiograph was abnormal although, at that time, no subjective symptoms were present. A physical examination showed blood pressure 128/60 mm Hg, pulse rate 84 bpm and arterial oxygen saturation (SpO 2 ) measured with a pulse oximeter of 90%. Her pulmonary second heart sound was accentuated. Laboratory test results revealed increased serum levels of C-reactive protein (2.3 mg/dl), B-type natriuretic peptide (1256 pg/ml) and sialylated carbonhydrate antigen KL-6 (583 U/ml). A chest radiograph revealed numerous micronodules throughout the entire lung field and obscured the cardiac shadow ( fig 1A). A CT scan of the chest showed consolidation and diffuse ground-glass opacities in both lungs, accompanied by dilated bronchi (fig 1B, upper panel). A marked enlargement of the right heart, retention of pleural and pericardial effusions and calcification involving the mediastinal and interlobular pleura and the pericardium were also observed ( fig 1B, lower panel). The ECG revealed a right bundle branch block accompanied by a tall R wave in aV R and V 1 , deep S and a small r in I and aV L and a persistent S or s in the left precardial leads. These findings suggested right ventricular hypertrophy. Spirometry showed restrictive ventilatory disturbances (vital capacity 51.6%, forced expiratory volume in 1 s 93.1%). Transthoracic echocardiography revealed a dilated right heart with tricuspid regurgitation (fig 1C, upper panel) where the right ventricle-right atrium pressure gradient was 81 mm Hg and the peak tricupsid regurgi...

Alveolar Surfactant Homeostasis and the Pathogenesis of Pulmonary Disease

“…Histological diagnoses associated with these disorders include congenital alveolar proteinosis, desquamative interstitial pneumonitis, chronic pneumonitis of infancy, nonspecific interstitial pneumonitis, and usual interstitial pneumonitis (9). Diffuse alveolar diseases, including idiopathic pulmonary fibrosis (IPF), pulmonary alveolar proteinosis (PAP) (10), and chronic pulmonary microlithiasis, have been associated, respectively, with mutations in SP-A (11) and the telomerase reverse transcriptase gene ( TERT ) (12, 13), in GM-CSF receptors (14, 15), and in the sodium/phosphate transport protein, SCL34A2 (16–18). Genetic causes, presentations, and courses of these disorders are relatively distinct.…”

“…The precise pathogenesis of this disorder, leading to the accumulation of calcium phosphate crystals in the alveolus, has been proposed to be related to the degradation of surfactant phospholipids and the release of phosphate into the alveolus, which, in turn, must be cleared from the lung by transport via SCL34A2. A number of mutations have been identified in the SCL34A2 gene, including missense, frameshift, gene termination, amino acid substitutions, and promoter deletions (16–18). Although the disorder generally presents with pulmonary symptoms, testicular microlithiasis, a cause of male sterility, has also been associated with mutations in SCL34A2 (16).…”

Pulmonary alveolar microlithiasis: a case report and review of the literature

“…In PAM, inactivating mutations in the SCL34A2 gene have only been discovered in recent years [3,4,7,8]. This gene encodes a type IIb sodium phosphate cotransporter that is expressed in the apical membrane of type II alveolar cells.…”

Bilateral Micronodular Pulmonary Infiltrate: Is It Important to Make a Histological Diagnosis?

“…It is inherited with an autosomal recessive pattern. 10,11 SLC34A2 is mainly expressed in the lung and mammary glands, and to a lesser extent in the intestine, kidneys, and prostate. This is the only phosphate transporter that is highly expressed in the lung, specifically in type II alveolar cells.…”