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Rough endoplasmic reticulum trafficking errors by different classes of mutant dentin sialophosphoprotein (DSPP) cause dominant negative effects in both dentinogenesis imperfecta and dentin dysplasia by entrapping normal DSPP.
J Bone Miner Res. 2012 Jun; 27(6):1309-21.JB

Abstract

Families with nonsyndromic dentinogenesis imperfecta (DGI) and the milder, dentin dysplasia (DD), have mutations in one allele of the dentin sialophosphoprotein (DSPP) gene. Because loss of a single Dspp allele in mice (and likely, humans) causes no dental phenotype, the mechanism(s) underling the dominant negative effects were investigated. DSPP mutations occur in three classes. (The first class, the mid-leader missense mutation, Y6D, was not investigated in this report.) All other 5′ mutations of DSPP result in changes/loss in the first three amino acids (isoleucine-proline-valine [IPV]) of mature DSPP or, for the A15V missense mutation, some retention of the hydrophobic leader sequence. All of this second class of mutations caused mutant DSPP to be retained in the rough endoplasmic reticulum (rER) of transfected HEK293 cells. Trafficking out of the rER by coexpressed normal DSPP was reduced in a dose-responsive manner, probably due to formation of Ca2+-dependent complexes with the retained mutant DSPP. IPV-like sequences begin many secreted Ca2+-binding proteins, and changing the third amino acid to the charged aspartate (D) in three other acidic proteins also caused increased rER accumulation. Both the leader-retaining A15V and the long string of hydrophobic amino acids resulting from all known frameshift mutations within the 3′-encoded Ca2+-binding repeat domain (third class of mutations) caused retention by association of the mutant proteins with rER membranes. More 5′ frameshift mutations result in longer mutant hydrophobic domains, but the milder phenotype, DD, probably due to lower effectiveness of the remaining, shorter Ca2+-binding domain in capturing normal DSPP protein within the rER. This study presents evidence of a shared underlying mechanism of capturing of normal DSPP by two different classes of DSPP mutations and offers an explanation for the mild (DD-II) versus severe (DGI-II and III) nonsyndromic dentin phenotypes. Evidence is also presented that many acidic, Ca2+-binding proteins may use the same IPV-like receptor/pathway for exiting the rER.

Authors+Show Affiliations

Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health/DHHS, 9000 Rockville Pike, Bethesda, MD, USA 20892-4320, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

22392858

Citation

von Marschall, Zofia, et al. "Rough Endoplasmic Reticulum Trafficking Errors By Different Classes of Mutant Dentin Sialophosphoprotein (DSPP) Cause Dominant Negative Effects in Both Dentinogenesis Imperfecta and Dentin Dysplasia By Entrapping Normal DSPP." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 27, no. 6, 2012, pp. 1309-21.
von Marschall Z, Mok S, Phillips MD, et al. Rough endoplasmic reticulum trafficking errors by different classes of mutant dentin sialophosphoprotein (DSPP) cause dominant negative effects in both dentinogenesis imperfecta and dentin dysplasia by entrapping normal DSPP. J Bone Miner Res. 2012;27(6):1309-21.
von Marschall, Z., Mok, S., Phillips, M. D., McKnight, D. A., & Fisher, L. W. (2012). Rough endoplasmic reticulum trafficking errors by different classes of mutant dentin sialophosphoprotein (DSPP) cause dominant negative effects in both dentinogenesis imperfecta and dentin dysplasia by entrapping normal DSPP. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 27(6), 1309-21. https://doi.org/10.1002/jbmr.1573
von Marschall Z, et al. Rough Endoplasmic Reticulum Trafficking Errors By Different Classes of Mutant Dentin Sialophosphoprotein (DSPP) Cause Dominant Negative Effects in Both Dentinogenesis Imperfecta and Dentin Dysplasia By Entrapping Normal DSPP. J Bone Miner Res. 2012;27(6):1309-21. PubMed PMID: 22392858.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rough endoplasmic reticulum trafficking errors by different classes of mutant dentin sialophosphoprotein (DSPP) cause dominant negative effects in both dentinogenesis imperfecta and dentin dysplasia by entrapping normal DSPP. AU - von Marschall,Zofia, AU - Mok,Seeun, AU - Phillips,Matthew D, AU - McKnight,Dianalee A, AU - Fisher,Larry W, PY - 2012/3/7/entrez PY - 2012/3/7/pubmed PY - 2012/9/14/medline SP - 1309 EP - 21 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J Bone Miner Res VL - 27 IS - 6 N2 - Families with nonsyndromic dentinogenesis imperfecta (DGI) and the milder, dentin dysplasia (DD), have mutations in one allele of the dentin sialophosphoprotein (DSPP) gene. Because loss of a single Dspp allele in mice (and likely, humans) causes no dental phenotype, the mechanism(s) underling the dominant negative effects were investigated. DSPP mutations occur in three classes. (The first class, the mid-leader missense mutation, Y6D, was not investigated in this report.) All other 5′ mutations of DSPP result in changes/loss in the first three amino acids (isoleucine-proline-valine [IPV]) of mature DSPP or, for the A15V missense mutation, some retention of the hydrophobic leader sequence. All of this second class of mutations caused mutant DSPP to be retained in the rough endoplasmic reticulum (rER) of transfected HEK293 cells. Trafficking out of the rER by coexpressed normal DSPP was reduced in a dose-responsive manner, probably due to formation of Ca2+-dependent complexes with the retained mutant DSPP. IPV-like sequences begin many secreted Ca2+-binding proteins, and changing the third amino acid to the charged aspartate (D) in three other acidic proteins also caused increased rER accumulation. Both the leader-retaining A15V and the long string of hydrophobic amino acids resulting from all known frameshift mutations within the 3′-encoded Ca2+-binding repeat domain (third class of mutations) caused retention by association of the mutant proteins with rER membranes. More 5′ frameshift mutations result in longer mutant hydrophobic domains, but the milder phenotype, DD, probably due to lower effectiveness of the remaining, shorter Ca2+-binding domain in capturing normal DSPP protein within the rER. This study presents evidence of a shared underlying mechanism of capturing of normal DSPP by two different classes of DSPP mutations and offers an explanation for the mild (DD-II) versus severe (DGI-II and III) nonsyndromic dentin phenotypes. Evidence is also presented that many acidic, Ca2+-binding proteins may use the same IPV-like receptor/pathway for exiting the rER. SN - 1523-4681 UR - https://www.unboundmedicine.com/medline/citation/22392858/Rough_endoplasmic_reticulum_trafficking_errors_by_different_classes_of_mutant_dentin_sialophosphoprotein__DSPP__cause_dominant_negative_effects_in_both_dentinogenesis_imperfecta_and_dentin_dysplasia_by_entrapping_normal_DSPP_ L2 - https://doi.org/10.1002/jbmr.1573 DB - PRIME DP - Unbound Medicine ER -