Mutations in the SLC34A2 gene are associated with the pulmonary alveolar
Huqun1,2, Shinyu Izumi3, Hitoshi Miyazawa1, Kuniaki Ishii4, Bine Uchiyama5, Tadashi
Ishida6, Sawako Tanaka7, Ryushi Tazawa2, Shunichiro Fukuyama1, Tomoaki Tanaka1,
Yoshiaki Nagai1, Akemi Yokote1, Hiroki Takahashi8, Toshihiko Fukushima9, Kunihiko
Kobayashi1, Hirofumi Chiba8, Makoto Nagata1, Susumu Sakamoto10, Koichiro Nakata10*,
Yuji Takebayashi9, Yoshihiko Shimizu11, Koichi Kaneko12, Michio Shimizu11, Minoru
Kanazawa1, Shosaku Abe8, Yoshikazu Inoue13, Seiichi Takenoshita9, Kunihiko Yoshimura10,
Koichiro Kudo14, Teruo Tachibana15, Toshihiro Nukiwa2 and Koichi Hagiwara1
1Department of Respiratory Medicine, 11Pathology, and 12Chest Surgery, Saitama Medical
School, Saitama 350-0495, Japan. 2Department of Respiratory Oncology and Molecular
Medicine, Tohoku University, Sendai 980-8575, Japan.
Medicine, 14Disease Control and Prevention Center, International Medical Center of Japan,
3Department of Pulmonary
Tokyo 162-8655, Japan.
University, Yamagata 990-9585, Japan. 5Department of Respiratory Medicine, Katta
4Department of Cardiovascular Pharmacology, Yamagata
General Hospital, Miyagi 989-0231, Japan.
Kurashiki Central Hospital, Okayama 710-8602, Japan．7Department of Respiratory
Medicine, Tama Hokubu Hospital, Tokyo 189-8511, Japan. 8The Third Department of
Internal Medicine, Sapporo Medical University, Sapporo 060-8556, Japan. 9Department
of Surgery II, Fukushima Medical University, Fukushima 960-1295, Japan. 10Department
6Department of Respiratory Medicine,
of Respiratory Medicine, Respiratory Center, Toranomon Hospital, Tokyo 105-8470, Japan.
13Clinical Research Center, National Hospital Organization, Kinki-chuo Chest Medical
Center, Osaka 591-8555, Japan. 15Osaka Kampo Medical Center, Osaka 556-0016, Japan
* Current address: Department of Respiratory Medicine, Toho University Omori Medical
Center, Tokyo 143-8541, Japan.
AJRCCM Articles in Press. Published on November 9, 2006 as doi:10.1164/rccm.200609-1274OC
Copyright (C) 2006 by the American Thoracic Society.
Correspondence should be addressed to:
Koichi Hagiwara, M.D., Ph.D.
Department of Respiratory Medicine
Saitama Medical University
38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan
Phone: +81-49-276-1319, FAX: +81-49-276-1635
Grant: This work is supported in part by the grant-in-aid for scientific research (No.
16659216) from the Japan Society of Promotion of Science.
Running head: SLC34A2 mutation in PAM patients
Descriptor number: 76
This article has an online data supplement, which is accessible from this issue’s table of
content online at www.atsjournals.org
The content of this work has been published in an abstract form in the Proceedings of the
American Thoracic Society, 3:A102, 2006.
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 a genome-wide SNP analysis using DNA from 3 patients, we have narrowed
the region where the candidate gene is located. From which we have identified a gene that
has mutations in all patients.
Measurements and Main results: We identified a candidate gene SLC34A2 that encodes a
type IIb sodium phosphate cotransporter is mutated in six of six patients investigated.
SLC34A2 is specifically expressed in the 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, SNPs
Pulmonary alveolar microlithiasis (PAM: OMIM265100) is a disease where
microliths are formed in the alveolar space (Figure 1A) (1) (2) (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 picture, diffuse nodular opacities formed by countless microliths are observed
(Figure 1B). PAM has been considered autosomal recessive, because it transmits
horizontally and inbreeding frequently coexists (3).
To identify the responsible gene for diseases with an autosomal recessive trait, the
homozygosity mapping approach has been successfully applied (6). The method
sometimes identified the gene from less than 10 patients. Recent development of
technology has enabled a high-density, genome-wide SNP analysis. The numbers of SNPs
genotyped is so large that a fine mapping of the candidate region for the gene is anticipated.
To efficiently utilize the SNP data, we have developed a novel algorithm based on the
homozygosity mapping, and used it to identify the responsible gene for PAM.
Preliminary results (7-9) and the final results of this study (10, 11) were presented
in the form of abstracts.
Subjects and ethical considerations
The study was approved by the Institutional Review Board of the participating
institutions. For all cases written informed consent was obtained from either the patient or
from a family member.
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). The scan was performed at the Australian
Genome Research Facility (Victoria, Australia) and AROS applied biotechnology (Aarhus