Biopolym. Cell. 2010; 26(1):13-22.
Mutations in the gene of human type IIb sodium-phosphate cotransporter SLC34A2
1Lituiev D. S., 1Kiyamova R. G.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680


Type IIb sodium-phosphate cotransporter (NaPi2b) provides phosphate intake in the cells of some epithelial tissues, osteoblasts and odontoblasts. Abnormal expression of NaPi2b has been detected in some types of epithelial tumors. An alteration in NaPi2b activity, caused by mutations in transporter gene SLC34A2, has been recently revealed in patients with pulmonary alveolar microlithiasis, an autosomal recessively inherited disease, characterized by deposition of calcium-phosphate precipitates in the lungs. In the present study we have combined the information about all mutations found to date in the coding sequence of SLC34A2 and its transcript, compiled their map, and analysed their relevance to the function of NaPi2b.
Keywords: SLC34A2 gene, inorganic phosphate transport, pulmonary alveolar microlithiasis, mutations, ovarian cancer


[1] Feild J. A., Zhang L., Brun K. A., Brooks D. P., Edwards R. M. Cloning and functional characterization of a sodiumdependent phosphate transporter expressed in human lung and small intestine Biochem. Biophys. Res. Communs 1999 258, N 3 P. 578–582.
[2] Xu H., Bai L., Collins J. F., Ghishan F. K. Molecular cloning, functional characterization, tissue distribution, and chromosomal localization of a human, small intestinal sodiumphosphate (Na+-Pi) transporter (SLC34A2) Genomics 1999 62, N 2 P. 281–284.
[3] Traebert M., Hattenhauer O., Murer H., Kaissling B., Biber J. Expression of type II Na-P(i) cotransporter in alveolar type II cells Am. J. Physiol 1999 277, N 5 P. 868–873.
[4] Xu Y., Yeung C. H., Setiawan I., Avram C., Biber J., Wagenfeld A., Lang F., Cooper T. G. Sodium-inorganic phosphate cotransporter NaPi-IIb in the epididymis and its potential role in male fertility studied in a transgenic mouse model Biol. Reprod 2003 69, N 4 P. 1135–1141.
[5] Miyoshi K., Shillingford J. M., Smith G. H., Grimm S. L., Wagner K. U., Oka T., Rosen J. M., Robinson G. W., Hennighausen L. Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium J. Cell Biol 2001 155, N 4 P. 531–542.
[6] Homann V., Rosin-Steiner S., Stratmann T., Arnold W. H., Gaengler P., Kinne R. K. Sodium-phosphate cotransporter in human salivary glands: molecular evidence for the involvement of NPT2b in acinar phosphate secretion and ductal phosphate reabsorption Arch. Oral Biol 2005 50, N 9 P. 759–768.
[7] Frei P., Gao B., Hagenbuch B., Mate A., Biber J., Murer H., Meier P. J., Stieger B. Identification and localization of sodium-phosphate cotransporters in hepatocytes and cholangiocytes of rat liver Am. J. Physiol. Gastrointest. Liver Physiol 2005 288, N 4 P. G771–778.
[8] Lundquist P. Odontoblast phosphate and calcium transport in dentinogenesis Swed. Dent. J. Suppl 2002 N 154 P. 1– 52.
[9] Lundquist P., Murer H., Biber J. Type II Na+-Pi Cotransporters in osteoblast mineral formation: regulation by inorganic phosphate Cell Physiol. Biochem 2007 19, N 1–4 P. 43–56.
[10] Murer H., Foster I., Biber J. The sodium phosphate cotransporter family SLC34 Pflugers Arch 2004 447, N 5 P. 763–778.
[11] Jarzab B., Wiench M., Fujarewicz K., Simek K., Jarzab M., Oczko-Wojciechowska M., Wloch J., Czarniecka A., Chmielik E., Lange D., Pawlaczek A., Szpak S., Gubala E., Swierniak A. Gene expression profile of papillary thyroid cancer: sources of variability and diagnostic implications Cancer Res 2005 65, N 4 P. 1587–1597.
[12] Gaiikza-Kulik M., Zebracka J., Szpak-Ulczok S., Czarniecka A. K., Kukulska A., Gubaia E., Stojcev Z., Wiench M. Expression of selected genes involved in transport of ions in papillary thyroid carcinoma. Endokrynologia Polska 2006 57, Suppl. A P. 26–31.
[13] Rangel L. B., Sherman-Baust C. A., Wernyj R. P., Schwartz D. R., Cho K. R., Morin P. J. Characterization of novel human ovarian cancer-specific transcripts (HOSTs) identified by serial analysis of gene expression Oncogene 2003 22, N 46 P. 7225–7232.
[14] Yin B. W., Kiyamova R., Chua R., Caballero O. L., Gout I., Gryshkova V., Bhaskaran N., Souchelnytskyi S., Hellman U., Filonenko V., Jungbluth A. A., Odunsi K., Lloyd K. O., Old L. J., Ritter G. Monoclonal antibody MX35 detects the membrane transporter NaPi2b (SLC34A2) in human carcinomas; a new target for cancer immunotherapy. Cancer Immun 2008 8 P. 3.
[15] Blanchard A., Shiu R., Booth S., Sorensen G., DeCorby N., Nistor A., Wong P., Leygue E., Myal Y. Gene expression profiling of early involuting mammary gland reveals novel genes potentially relevant to human breast cancer Front. Biosci 2007 12 P. 2221–2232.
[16] Kopantzev E. P., Monastyrskaya G. S., Vinogradova T. V., Zinovyeva M. V., Kostina M. B., Filyukova O. B., Tonevitsky A. G., Sukhikh G. T., Sverdlov E. D. Differences in gene expression levels between early and later stages of human lung development are opposite to those between normal lung tissue and non-small lung cell carcinoma Lung Cancer 2008 62, N 1 P. 23–34.
[17] Otsuki T., Ota T., Nishikawa T., Hayashi K., Suzuki Y., Yamamoto J., Wakamatsu A., Kimura K., Sakamoto K., Hatano N., Kawai Y., Ishii S., Saito K., Kojima S., Sugiyama T., Ono T., Okano K., Yoshikawa Y., Aotsuka S., Sasaki N., Hattori A., Okumura K., Nagai K., Sugano S., Isogai T. Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries DNA Res 2005 12, N 2 P. 117–126 .
[18] Corut A., Senyigit A., Ugur S. A., Altin S., Ozcelik U., Calisir H., Yildirim Z., Gocmen A., Tolun A. Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis Am. J. Hum. Genet 2006 79, N 4 P. 650–656.
[19] Huqun, Izumi S., Miyazawa H., Ishii K., Uchiyama B., Ishida T., Tanaka S., Tazawa R., Fukuyama S., Tanaka T., Nagai Y., Yokote A., Takahashi H., Fukushima T., Kobayashi K., Chiba H., Nagata M., Sakamoto S., Nakata K., Takebayashi Y., Shimizu Y., Kaneko K., Shimizu M., Kanazawa M., Abe S., Inoue Y., Takenoshita S., Yoshimura K., Kudo K., Tachibana T., Nukiwa T., Hagiwara K. Mutations in the SLC34A2 gene are associated with the pulmonary alveolar microlithiasis Am. J. Respirat. and Crit. Care Med 2007 175, N 3 P. 263–268.
[20] Werner A., Dehmelt L., Nalbant P. Na+-dependent phosphate cotransporters: the NaPi protein families. Exp. Biol 1998 201, N 23 P. 3135–3142.
[21] Kohl B., Wagner C. A., Huelseweh B., Busch A. E., Werner A. The Na+–phosphate cotransport system (NaPi-II) with a cleaved protein backbone: implications on function and membrane insertion J. Physiol 1998 508, N 2 P. 341– 350.
[22] Karim-Jimenez Z., Hernando N., Biber J., Murer H. Requirement of a leucine residue for (apical) membrane expression of type IIb NaPi cotransporter Proc. Nat. Acad. Sci. USA 2000 97, N 6 P. 2916–2921.
[23] Gisler S. M., Stagljar I., Traebert M., Bacic D., Biber J., Murer H. Interaction of the type IIa Na/Pi cotransporter with PDZ proteins J. Biol. Chem 2001 276, N 12 P. 9206– 9213.
[24] Frappart L., Remy I., Lin H. C., Bremond A., Raudrant D., Grousson B., Vauzelle J. L. Different types of microcalcifications observed in breast pathology. Correlations with histopathological diagnosis and radiological examination of operative specimens Virchows Arch. a Pathol. Anat. Histopathol 1986 410, N 3 P. 179–187.
[25] Maki M., Hirota S., Kaneko Y., Morohoshi T. Expression of osteopontin messenger RNA by macrophages in ovarian serous papillary cystadenocarcinoma: a possible association with calcification of psammoma bodies Pathol. Int 2000 50, N 7 P. 531–535.
[26] Morgan M. P., Cooke M. M., Christopherson P. A., Westfall P. R., McCarthy G. M. Calcium hydroxyapatite promotes mitogenesis and matrix metalloproteinase expression in human breast cancer cell lines Mol. Carcinog 2001 32, N 3 P. 111–117.
[27] Kiyamova R., Gryshkova V., Ovcharenko G., Lituyev D., Malyuchik S., Usenko V., Khozhayenko Y., Gurtovyy V., Yin B., Ritter G., Old L., Filonenko V., Gout I. Development of monoclonal antibodies specific for the human sodiumdependent phosphate cotransporter NaPi2b Hybridoma 2008 27, N 4 P. 277–284.
[28] Gryshkova V. S., Lituyev D. S., Filonenko V. V., Kiyamova R. G. Creation of cellular models for the analysis of sodium-dependent phosphate transporter NaPi2b, a potential marker for ovarian cancer Biopolym. cell 2009 25, N 2 P. 95–100.
[29] Kimchi-Sarfaty C., Oh J. M., Kim I.-W., Sauna Z. E., Calcagno A. M., Ambudkar S. V., Gottesman M. M. A «silent» polymorphism in the MDR1 gene changes substrate specificity Science 2007 315, N 5811 P. 525–528.
[30] Ball E. V., Stenson P. D., Abeysinghe S. S., Krawczak M., Cooper D. N., Chuzhanova N. A. Microdeletions and microinsertions causing human genetic disease: common mechanisms of mutagenesis and the role of local DNA sequence complexity Hum. Mutat 2005 26, N 3 P. 205–213.
[31] Abeysinghe S. S., Chuzhanova N., Krawczak M., Ball E. V., Cooper D. N. Translocation and gross deletion breakpoints in human inherited disease and cancer I: Nucleotide composition and recombination-associated motifs Hum. Mutat 2003 22, N 3 P. 229–244.
[32] Van den Hurk W. H., Willems H. J. J., Bloemen M., Martens G. J. M. Novel frameshift mutations near short simple repeats J. Biol. Chem 2001 276, N 15 P. 11496–11498.
[33] Niu X., Zheng W., Lu B. R., Ren G., Huang W., Wang S., Liu J., Tang Z., Luo D., Wang Y., Liu Y. An unusual posttranscriptional processing in two betaine aldehyde dehydrogenase loci of cereal crops directed by short, direct repeats in response to stress conditions Plant Physiol 2007 143, N 4 P. 1929–1942.
[34] Fan J., Niu X., Wang Y., Ren G., Zhuo T., Yang Y., Lu B.R., Liu Y. Short, direct repeats (SDRs)-mediated post-transcriptional processing of a transcription factor gene OsVP1 in rice (Oryza sativa) J. Exp. Bot 2007 58, N 13 P. 3811– 3817.
[35] Blom N., Gammeltoft S., Brunak S. Sequenceand structurebased prediction of eukaryotic protein phosphorylation sites J. Mol. Biol 1999 294, N 5 P. 1351–1362.