Published ahead of print on November 9, 2006, doi:10.1164/rccm.200609-1274OC
American Journal of Respiratory and Critical Care Medicine Vol 175. pp. 263-268, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200609-1274OC
Mutations in the SLC34A2 Gene Are Associated with Pulmonary Alveolar Microlithiasis
Huqun,
Shinyu Izumi,
Hitoshi Miyazawa,
Kuniaki Ishii,
Bine Uchiyama,
Tadashi Ishida,
Sawako Tanaka,
Ryushi Tazawa,
Shunichiro Fukuyama,
Tomoaki Tanaka,
Yoshiaki Nagai,
Akemi Yokote,
Hiroki Takahashi,
Toshihiko Fukushima,
Kunihiko Kobayashi,
Hirofumi Chiba,
Makoto Nagata,
Susumu Sakamoto,
Koichiro Nakata,
Yuji Takebayashi,
Yoshihiko Shimizu,
Koichi Kaneko,
Michio Shimizu,
Minoru Kanazawa,
Shosaku Abe,
Yoshikazu Inoue,
Seiichi Takenoshita,
Kunihiko Yoshimura,
Koichiro Kudo,
Teruo Tachibana,
Toshihiro Nukiwa and
Koichi Hagiwara
Departments of Respiratory Medicine, Pathology, and Chest Surgery, Saitama Medical University, Saitama; Department of Respiratory Oncology and Molecular Medicine, Tohoku University, Sendai; Department of Pulmonary Medicine, Disease Control and Prevention Center, International Medical Center of Japan; Department of Respiratory Medicine, Tama Hokubu Hospital; Department of Respiratory Medicine, Respiratory Center, Toranomon Hospital, Tokyo; Department of Cardiovascular Pharmacology, Yamagata University, Yamagata; Department of Respiratory Medicine, Katta General Hospital, Miyagi; Department of Respiratory Medicine, Kurashiki Central Hospital, Okayama; Third Department of Internal Medicine, Sapporo Medical University, Sapporo; Department of Surgery II, Fukushima Medical University, Fukushima; Clinical Research Center, National Hospital Organization, Kinki-chuo Chest Medical Center; and Osaka Kampo Medical Center, Osaka, Japan
Correspondence and requests for reprints should be addressed to Koichi Hagiwara, M.D., Ph.D., Professor, Department of Respiratory Medicine, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350–0495, Japan. E-mail: hagiwark{at}saitama-med.ac.jp
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ABSTRACT
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Rationale: Pulmonary alveolar microlithiasis is an autosomal recessive disorder in which microliths are formed in the alveolar space.
Objectives: To identify the responsible gene that causes pulmonary alveolar microlithiasis.
Methods: By means of a genomewide single-nucleotide polymorphism analysis using DNA from three patients, we have narrowed the region in which the candidate gene is located. From this region, we have identified a gene that has mutations in all patients with pulmonary alveolar microlithiasis.
Measurements and Main Results: We identified a candidate gene, SLC34A2, that encodes a type IIb sodium phosphate cotransporter and that is mutated in six of six patients investigated. SLC34A2 is specifically expressed in type II alveolar cells, and the mutations abolished the normal gene function.
Conclusion: Mutations in the SLC34A2 gene that abolish normal gene function cause pulmonary alveolar microlithiasis.
Key Words: pulmonary alveolar microlithiasis • homozygosity mapping • GeneChip • single-nucleotide polymorphisms
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AT A GLANCE COMMENTARY
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Scientific Knowledge on the Subject
Pulmonary alveolar microlithiasis is an autosomal recessive disorder in which microliths are formed in the alveolar space. However, the responsible gene has not been identified.
What This Study Adds to the Field
Mutation of the SLC34A2 gene that encodes the sodium-dependent phosphate transporter causes pulmonary alveolar microlithiasis.
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Pulmonary alveolar microlithiasis (PAM; OMIM [Online Mendelian Inheritance in Man] 265100) is a disease in which microliths are formed in the alveolar space (Figure 1A) (1–3). Ever since the first description by Puhr in 1933 (4), over 500 cases have been reported worldwide, including more than 100 cases in Japan (5). Patients remain symptom free until middle age when chronic respiratory failure and cardiopulmonary decompensation develop. In a chest X-ray image, diffuse fine nodular opacities formed by countless microliths are observed (Figure 1B). PAM has been considered to be an autosomal recessive disorder, because it transmits horizontally and inbreeding frequently coexists (3).
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Figure 1. Microscopic and chest X-ray images of pulmonary alveolar microlithiasis (PAM). (A) A thin section of the decalcified lung tissue from patient 5 stained with hematoxylin and eosin. Concentric lamellar structures are decalcified remnants of microliths that occupied the entire alveolar space (arrows). Alveolar walls are thickened and many inflammatory cells have infiltrated into the parenchyma, indicating the presence of chronic inflammation. (B) A chest X-ray image of patient 2. Countless microliths form diffuse fine nodular opacities. The "snowstorm" appearance is very characteristic.
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To identify the responsible gene for diseases with an autosomal recessive trait, the homozygosity mapping approach has been successfully applied (6). This method has identified the gene from fewer than 10 patients. Recent technological development has enabled high-density, genomewide single-nucleotide polymorphism (SNP) analysis. The numbers of SNPs genotyped are so great that fine mapping of the candidate region for the gene is anticipated. To efficiently use the SNP data, we have developed a novel algorithm based on the homozygosity mapping, and have used it to identify the gene responsible for PAM.
Preliminary (7–9) and final results of this study (10, 11) have been presented in the form of abstracts.
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METHODS
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Subjects and Ethical Considerations
The study was approved by the institutional review boards of the participating institutions. For all cases, written, informed consent was obtained from either the patient or from a family member.
Genotyping
We isolated genomic DNA either from blood samples or from paraffin-embedded tissues using standard protocols. For the whole-genome scan, we used the GeneChip Human Mapping 100k set (Affymetrix, Santa Clara, CA). The scan was performed at the Australian Genome Research Facility (Victoria, Australia) and AROS Applied Biotechnology (Aarhus Nord, Denmark). Computer analyses of the GeneChip results were performed using custom programs written in our laboratory (source codes available on request). The nucleotide sequencing of the individual exons of SLC34A2 was performed using an ABI 377 automated sequencer (Applied Biosystems, Foster City, CA).
Frequency of the Mutation of SLC34A2 in the Japanese Population
Using a 5' nuclease assay (for exon 7) or the PNA-LNA (peptide nucleic acid–locked nucleic acid) polymerase chain reaction clamp (for exon 8) (12), we investigated the presence of the mutations in genomic DNA from 188 normal volunteers. The amplification signals were detected using Smart Cycler II (Cepheid, Sunnyvale, CA).
Microinjection into Xenopus oocytes
We subcloned cDNA of the wild-type SLC34A2 and its mutants seen in the patients into pcDNA3.1, and capped RNA was transcribed in vitro from the T7 promoter. Integrity of RNA was confirmed by gel electrophoresis. Expression of the proteins on the surface of Xenopus oocytes and functional study were performed as described (13). In short, after being microinjected with 46 nl of water containing 46 ng of RNA, oocytes were then incubated in modified Barth's solution at 18°C for 3 d. In the phosphate transport assay, oocytes, seven for each injection group, were washed in Na+-free ND-100 solution containing 0.5 mM KH2PO4 (25 mCi/ml 32P-orthophosphoric acid) for 60 min. After washing three times with cold Na+-free ND-100 solution (100 mM NaCl, 2 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 5 mM N-2-hydroxyethylpiperazine-N'-ethane sulfonic acid [HEPES]), oocytes were lysed in 0.2 ml of 10% sodium dodecyl sulfate and the radioactivity was counted. In the electrophysiologic recording, whole-cell currents were measured using a conventional, 2-microelectrode-voltage clamp method with a holding potential of –50 mV. Under a continuous recording of current, oocytes were serially superfused with ND-100 solution (pH 6.6), ND-100 solution containing 1 mM NaH2PO4 (pH 6.6), and then ND-100 solution (pH 6.6).
In Situ Hybridization and Immunohistochemistry
Paraffin-embedded normal human lung tissue was serially thin sectioned, and we investigated the expression of SLC34A2 RNA and surfactant protein A (SP-A). A part of the open reading frame of SLC34A2 cDNA was amplified using primers tagged with the T7 promoter sequence. Fluorescent-labeled RNA probes were made using an RNA labeling kit (Hoffmann-La Roche, Basel, Switzerland). In situ hybridization was performed and the signal was detected by GenPoint fluorescein kit (Dako Cytomation, Glostrup, Denmark). SP-A protein was detected using a mouse anti-human SP-A monoclonal antibody (Dako Cytomation), together with a horseradish-labeled goat anti-mouse IgG antibody (Santa Cruz Biotechnology, Santa Cruz, CA) and 3,3'-diaminobenzidine chromogen.
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RESULTS
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We identified 6 cases of PAM from the case reports in Japan. Three patients were alive. Three had died; however, their paraffin-embedded tissues were available (Table 1 and Figure E1 of the online supplement). We were able to obtain samples from six of these patients (three still alive and three dead). Of the three live patients, two (patients 1 and 2) were children of parents who were first cousins. The other (patient 3) was from a family in which three patients were clustered and thus inbreeding was strongly suspected, considering that the inbreeding rate has been historically high in Japan (14). These three patients were unrelated and from different parts of Japan. To identify the gene responsible for PAM (the PAM gene) from a small number of samples, genomic DNA isolated from the peripheral blood of three live patients was investigated using the GeneChip mapping set (Affymetrix), which has the ability to analyze 100,000 SNPs at one time. The results were analyzed according to the homozygosity mapping strategy (6), which anticipates the candidate gene will be located in the homozygosity segment in which both copies of homologous chromosomes are derived from a single ancestral chromosome. To apply the strategy to genomewide SNP genotyping data, we took the following approach. We considered that the homozygosity segment could be detected as a stretch of homozygous SNPs (SHS) in which every SNP type is homozygous. We also considered that if the significance of SHS is appropriately defined, the homozygosity segment will be clearly delineated, and this should allow us to narrow the candidate region for the PAM gene geometrically by serially obtaining intersections of SHS for each patient. We defined significant SHS as a run of homozygous SNPs where the product of the frequencies of homozygosity reported in the Asian population for the individual SNPs is less than 1 in 100,000 (see the online supplement). Significant SHS of patients 1 through 3 are shown in Figures 2B–2D. A mathematical calculation revealed that the probability that the PAM gene is contained in significant SHS is 0.999 for the child of the first-cousin marriage and 0.94 even for the child of the 20th-cousin marriage (see Table E1). Consequently, the overlaps of significant SHS for patients 1 and 2 (Figure 2E) have a probability of 0.998 (= 0.9992) of containing the PAM gene. We assumed the presence of the inbreeding in patient 3, and further narrowed the region, giving candidate regions with a total length of 12.4 Mb (see Table E2). The region contained 50 genes, of which 31 genes had known or suspected functions. SLC34A2 (Unigene Hs. 479372: solute carrier family 34 [sodium phosphate], member 2) (15, 16), a transporter of sodium phosphate, was the only gene that was directly related to calcium or phosphate metabolism. We thus investigated the individual exons of SLC34A2 and found that five of five patients had homozygous mutations, whereas 10 normal volunteers did not, indicating that a mutation in SLC34A2 is significantly associated with PAM (p < 2.5 x 10–4 by the Fisher's exact test). To determine the frequency of the mutant genes in the Japanese population, we screened the genomic DNA from 188 volunteers (i.e., 376 control chromosomes) for the two mutations found, and all samples were negative. This indicates that the frequency of a chromosome with a mutant gene in the general population is less than 0.008 (a 95% confidence interval). In patients 3 and 5, an aberrant sequence replaced a part of exon 7 (Figure 3A), causing a frameshift that produces a truncated protein. In patients 1, 2, 4, and 6, a G nucleotide in the donor site of the splicing signal of exon 8 is replaced with an A (Figure 3B), which causes splicing failure, leading to a premature termination of the protein. The truncated proteins are about half the size of the full-length protein (Figure 3C). Patients 1 and 2 shared a conserved haplotype in a 1.1-Mb–long region, whereas patients 3 and 5 shared a 150-kb–long region (Figure 4). This suggests that each mutation is derived from a single founder.
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Figure 2. Narrowing the candidate chromosomal regions for the PAM gene using significant stretches of homozygous SNPs (SHS). (A) Result of SNP typing for patient 1. Each vertical bar indicates an SNP aligned according to its location on the chromosome. A homozygous SNP is shown in black and a heterozygous SNP is in light gray. Gray arrows under each panel indicate the direction of the short and the long arms of the chromosomes. (B) Significant SHS (shown in black) for patient 1 who is a child of a first-cousin marriage. (C) Significant SHS for patient 2. (D) Significant SHS for patient 3. (E) The overlap of significant SHS for patients 1 and 2. Data from only two patients considerably narrowed the candidate regions. (F) The overlap of significant SHS for patients 1, 2, and 3. An arrow indicates the significant SHS located on chromosome 4 that contained the PAM gene (SLC34A2).
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Figure 3. SLC34A2 mutations in patients. (A) A deletion-insertion mutation in patients 3 and 5. Small duplications in the nucleotide sequence in the same (gray arrows) and in the opposite (black arrows) directions suggest a complicated mutation event. (B) Mutation observed in patients 1, 2, 4, and 6. The 3' end of the exon 8 sequence is enclosed with a translated amino acid sequence shown above. A conserved splicing donor sequence (GT) is underlined. Solid, inverted triangles indicate the point of mutation resulting in a G to A transition. The nucleotide change abrogates normal splicing and the translation continues into intron 8 to add 10 aberrant amino acids before being terminated by an occasional stop codon. (C) Mutant proteins predicted from the mutant sequences. Structures of normal protein and protein produced by the mutation in exon 7 and in exon 8 are depicted. Na/Pi cotrans = a sodium phosphate cotransporter motif (pfam 02,690). Black boxes under normal protein are predicted transmembrane domains. Numbers shown on mutant proteins are (numbers of SLC34A2-derived amino acids in the mutant protein) plus (numbers of aberrant amino acids added by a frameshift resulting from a mutation). Sequences that exist only in the mutant proteins are indicated by light-gray boxes.
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Figure 4. Haplotype analysis of the patients. Coarse scale (upper panel) and fine scale (lower panel) analyses are shown. We individually amplified each SNP site and genotyped by sequencing. Samples of patients 4 and 6 were excluded from the analysis: patient 4 is the younger sister of patient 1 and the same haplotype was expected. DNA of sufficient quality was not obtained from the paraffin-embedded tissue of patient 6 for completion of all SNP analyses. Regions conserved for patients 1 and 2 or for patients 3 and 5 are indicated by brackets. All SNPs have a minor allele frequency of more than 0.2. Blue and yellow squares show common alleles and rare alleles, respectively. Heterozygous sites are indicated by both colors. SNP sites included in the SLC34A2 gene are boxed. SNP rsIDs used in both coarse and fine analyses are in bold letters. N = normal control; Pt = patient. The headings Gene symbol and SNP rsID indicate, respectively, the official symbol and an SNP ID used in the Genbank database (www.ncbi.nlm.nih.gov).
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Because SLC34A2 is a membrane protein with eight predicted transmembrane domains, proteins lacking five of these domains are likely to lose the normal function. To confirm this, we cloned the wild-type and the mutant SLC34A2 cDNA individually into the pcDNA3.1 vector (Invitrogen, Carlsbad, CA). Capped RNA was transcribed in vitro from the T7 promoter and microinjected into the oocytes of Xenopus laevis. The wild-type SLC34A2 transported phosphate in the presence of sodium, whereas the mutants did not (Figure 5A). SLC34A2 cotransports sodium and phosphate into the cells (15) with a stoichiometry of  , and thus produces inward current. The wild-type SLC34A2 elicited inward current with the addition of NaH2PO4, whereas mutants did not (Figure 5B). The proteins with the mutations seen in the patients abolished the normal transporter function.
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Figure 5. Functional analysis of SLC34A2 mutants. (A) Phosphate transport assay. Xenopus oocytes microinjected with transcribed in vitro wild-type RNA, mutant RNA, or water were assayed for phosphate uptake. (B) Electrophysiologic measurement. Microinjected oocytes superfused in ND-100 solution (pH 6.6; 100 mM NaCl, 2 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 5 mM N-2-hydroxyethylpiperazine-N'-ethane sulfonic acid [HEPES]) were exposed to ND-100 solution containing 1 mM NaH2PO4 (pH 6.6) (open arrows) and then washed with ND-100 solution (pH 6.6) (solid arrows). Patient 1, Patient 3 = mutants observed in patients 1 and 3; WT = wild type.
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DISCUSSION
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SLC34A2 is expressed mainly in lung and mammary gland and to a lesser extent in intestine, kidney, and prostate (15). SLC34A2 is the only phosphate transporter that is highly expressed in the lung (15), where the expression is observed specifically in type II alveolar cells (Figure 6) (17). By immunohistochemistry, SLC34A2 protein was observed in the apical pole of the cells (18). The type II cells produce pulmonary surfactant, of which phospholipids are essential constituents. Outdated surfactant is taken up by type II cells for recycling and degradation and by alveolar macrophages for degradation (19). Degraded phospholipids release phosphate that should be cleared from the alveolar space. Dysfunction of SLC34A2 may reduce the clearance of phosphate and may lead to the formation of microliths. In many cases of PAM, the lung is the only organ affected (1–3). Other organs may have phosphate transporters with redundant functions.
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Figure 6. In situ hybridization. Cells expressing SLC34A2 were investigated using serial sections of normal lung tissue. Antisense probe: in situ hybridization using SLC34A2 antisense probe. SP-A antibody: immunohistochemical detection of SP-A (a marker of type II alveolar cells). Arrows indicate cells detected by both methods.
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We have demonstrated that (1) homozygous inactivating mutations in SLC34A2 are present in patients with PAM, (2) SLC34A2 is highly expressed in alveolar type II cells, and (3) loss of the normal function of SLC34A2 can explain the pathophysiology of PAM. On the basis of this evidence, we conclude that SLC34A2 is the PAM gene.
Recently, Corut and colleagues (20) reported that SLC34A2 is mutated in Turkish patients with PAM. The result is consistent with ours and confirms that SLC34A2 is the causative gene for PAM.
No effective treatment for PAM currently exists, with the exception of lung transplantation. Disodium etidronate inhibits microcrystal growth of hydroxyapatite and thus inhibits ectopic calcification. This drug has been used to treat PAM, with little or no benefit (21–23). Our results suggest that remedies that target phosphate metabolism rather than calcium metabolism may be beneficial for the treatment of PAM.
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Acknowledgments
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The authors thank Dr. Roger Reddel, Children's Medical Research Institute, Sydney, Australia, for his helpful collaboration. They thank Dr. Yasushi Okazaki for detailed scientific discussion.
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FOOTNOTES
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Supported in part by the grant-in-aid for scientific research (No. 16659216) from the Japan Society for the Promotion of Science.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.200609-1274OC on November 9, 2006
Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
Received in original form September 7, 2006;
accepted in final form November 7, 2006
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ABSTRACT
AT A GLANCE COMMENTARY