Skip to main content
SpringerLink
Log in

The cld mutation: narrowing the critical chromosomal region and selecting candidate genes

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

Combined lipase deficiency (cld) is a recessive, lethal mutation specific to the t w73 haplotype on mouse Chromosome 17. While the cld mutation results in lipase proteins that are inactive, aggregated, and retained in the endoplasmic reticulum (ER), it maps separately from the lipase structural genes. We have narrowed the gene critical region by about 50% using the t w18 haplotype for deletion mapping and a recombinant chromosome used originally to map cld with respect to the phenotypic marker tf. The region now extends from 22 to 25.6 Mbp on the wild-type chromosome, currently containing 149 genes and 50 expressed sequence tags (ESTs). To identify the affected gene, we have selected candidates based on their known role in associated biological processes, cellular components, and molecular functions that best fit with the predicted function of the cld gene. A secondary approach was based on differences in mRNA levels between mutant (cld/cld) and unaffected (+/cld) cells. Using both approaches, we have identified seven functional candidates with an ER localization and/or an involvement in protein maturation and folding that could explain the lipase deficiency, and six expression candidates that exhibit large differences in mRNA levels between mutant and unaffected cells. Significantly, two genes were found to be candidates with regard to both function and expression, thus emerging as the strongest candidates for cld. We discuss the implications of our mapping results and our selection of candidates with respect to other genes, deletions, and mutations occurring in the cld critical region.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.

Similar content being viewed by others

References

  • Ailhaud G (1990) Cellular and secreted lipoprotein lipase revisited. Clin Biochem 23:343–347

    Article  PubMed  CAS  Google Scholar 

  • Appenzeller C, Andersson H, Kappeler F, Hauri HP (1999) The lectin ERGIC-53 is a cargo transport receptor for glycoproteins. Nat Cell Biol 1:330–334

    Article  PubMed  CAS  Google Scholar 

  • Ardlie KG (1998) Putting the brake on drive: meiotic drive of t haplotypes in natural populations of mice. Trends Genet 14:189–193

    Article  PubMed  CAS  Google Scholar 

  • Artzt K (1984) Gene mapping within the T/t complex of the mouse. III: t-Lethal genes are arranged in three clusters on chromosome 17. Cell 39:565–572

    Article  PubMed  CAS  Google Scholar 

  • Artzt K, McCormick P, Bennett D (1982a) Gene mapping within the T/t complex of the mouse. I. t-Lethal genes are nonallelic. Cell 28:463–470

    Article  CAS  Google Scholar 

  • Artzt K, Shin HS, Bennett D (1982b) Gene mapping within the T/t complex of the mouse. II. Anomalous position of the H-2 complex in t haplotypes. Cell 28:471–476

    Article  CAS  Google Scholar 

  • Artzt K, Barlow D, Dove WF, Fischer L, Klein J, et al. (1991) Maps of mouse chromosome 17: first report. Mamm Genome 1:5–29

    Article  CAS  Google Scholar 

  • Babiarz B, Garrisi GJ, Bennett D (1982) Genetic analysis of the tw73 haplotype of the mouse using deletion mutations: evidence for a parasitic lethal mutation. Genet Res 39:111–120

    Article  PubMed  CAS  Google Scholar 

  • Barclay J, King TF, Crossley PH, Barnard RC, Larin Z, et al. (1996) Physical analysis of the region deleted in the tw18 allele of the mouse tcl-4 complementation group. Genomics 36:39–46

    Article  PubMed  CAS  Google Scholar 

  • Ben-Zeev O, Doolittle MH (2004) Maturation of hepatic lipase. Formation of functional enzyme in the endoplasmic reticulum is the rate-limiting step in its secretion. J Biol Chem 279:6171–6181

    Article  PubMed  CAS  Google Scholar 

  • Ben-Zeev O, Mao HZ, Doolittle MH (2002) Maturation of lipoprotein lipase in the endoplasmic reticulum. Concurrent formation of functional dimers and inactive aggregates. J Biol Chem 277:10727–10738

    Article  PubMed  CAS  Google Scholar 

  • Bennett D (1975) The T-locus of the mouse. Cell 6:441–454

    Article  Google Scholar 

  • Bergstrom DE, Bergstrom RA, Munroe RJ, Lee BK, Browning VL, et al. (2003) Overlapping deletions spanning the proximal two-thirds of the mouse t complex. Mamm Genome 14:817–829

    Article  PubMed  CAS  Google Scholar 

  • Boedeker JC, Doolittle MH, White AL (2001) Differential effect of combined lipase deficiency (cld/cld) on human hepatic lipase and lipoprotein lipase secretion. J Lipid Res 42:1858–1864

    PubMed  CAS  Google Scholar 

  • Briquet-Laugier V, Ben-Zeev O, White A, Doolittle MH (1999) cld and lec23 are disparate mutations that affect maturation of lipoprotein lipase in the endoplasmic reticulum. J Lipid Res 40:2044–2058

    PubMed  CAS  Google Scholar 

  • Coleman T, Seip RL, Gimble JM, Lee D, Maeda N, et al. (1995) COOH-terminal disruption of lipoprotein lipase in mice is lethal in homozygotes, but heterozygotes have elevated triglycerides and impaired enzyme activity. J Biol Chem 270:12518–12525

    Article  PubMed  CAS  Google Scholar 

  • Davis RC, Ben-Zeev O, Martin D, Doolittle MH (1990) Combined lipase deficiency in the mouse. Evidence of impaired lipase processing and secretion. J Biol Chem 265:17960–17966

    PubMed  CAS  Google Scholar 

  • Dietrich WF, Miller JC, Steen RG, Merchant M, Damron D, et al. (1994) A genetic map of the mouse with 4,006 simple sequence length polymorphisms. Nat Genet 7:220–245

    Article  PubMed  CAS  Google Scholar 

  • Ebersole T, Lai F, Artzt K (1992) New molecular markers for the distal end of the t-complex and their relationships to mutations affecting mouse development. Genetics 131:175–182

    PubMed  CAS  Google Scholar 

  • Fox HS, Silver LM, Martin GR (1984) An alpha globin pseudogene is located within the mouse t complex. Immunogenetics 19:125–130

    Article  PubMed  CAS  Google Scholar 

  • Ha H, Howard CA, Yeom YI, Abe K, Uehara H, et al. (1991) Several testis-expressed genes in the mouse t-complex have expression differences between wild-type and t-mutant mice. Dev Genet 12:318–332

    Article  PubMed  CAS  Google Scholar 

  • Hammer MF, Schimenti J, Silver LM (1989) Evolution of mouse chromosome 17 and the origin of inversions associated with t haplotypes. Proc Natl Acad Sci USA 86:3261–3265

    Article  PubMed  CAS  Google Scholar 

  • Hauri HP, Kappeler F, Andersson H, Appenzeller C (2000) ERGIC-53 and traffic in the secretory pathway. J Cell Sci 113(Pt 4):587–596

    PubMed  CAS  Google Scholar 

  • Helenius A, Aebi M (2004) Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem 73:1019–1049

    Article  PubMed  CAS  Google Scholar 

  • Herrmann BG, Koschorz B, Wertz K, McLaughlin KJ, Kispert A (1999) A protein kinase encoded by the t complex responder gene causes non-mendelian inheritance. Nature 402:141–146

    Article  PubMed  CAS  Google Scholar 

  • Himmelbauer H, Pohlschmidt M, Snarey A, Germino GG, Weinstat-Saslow D, et al. (1992) Human-mouse homologies in the region of the polycystic kidney disease gene (PKD1). Genomics 13:35–38

    Article  PubMed  CAS  Google Scholar 

  • Himmelbauer H, Harvey RP, Copeland NG, Jenkins NA, Silver LM (1994) High-resolution genetic analysis of a deletion on mouse chromosome 17 extending over the fused, tufted, and homeobox Nkx2-5 loci. Mamm Genome 5:814–816

    Article  PubMed  CAS  Google Scholar 

  • Homanics GE, de Silva HV, Osada J, Zhang SH, Wong H, et al. (1995) Mild dyslipidemia in mice following targeted inactivation of the hepatic lipase gene. J Biol Chem 270:2974–2980

    Article  PubMed  CAS  Google Scholar 

  • Howell GR, Bergstrom RA, Munroe RJ, Masse J, Schimenti JC (2004) Identification of a cryptic lethal mutation in the mouse t(w73) haplotype. Genet Res 84:153–159

    Article  PubMed  CAS  Google Scholar 

  • Kim PS, Arvan P (1998) Endocrinopathies in the family of endoplasmic reticulum (ER) storage diseases: disorders of protein trafficking and the role of ER molecular chaperones. Endocr Rev 19:173–202

    Article  PubMed  CAS  Google Scholar 

  • Klein J, Sipos P, Figueroa F (1984) Polymorphism of t-complex genes in European wild mice. Genet Res Camb 44, 39–46

    Google Scholar 

  • Lowe ME (2002) The triglyceride lipases of the pancreas. J Lipid Res 43:2007–2016

    Article  PubMed  CAS  Google Scholar 

  • Martin GR, Silver LM, Fox HS, Joyner AL (1987) Establishment of embryonic stem cell lines from preimplantation mouse embryos homozygous for lethal mutations in the t-complex. Dev Biol 121:20–28

    Article  PubMed  CAS  Google Scholar 

  • Mead JR, Irvine SA, Ramji DP (2002) Lipoprotein lipase: structure, function, regulation, and role in disease. J Mol Med 80:753–769

    Article  PubMed  CAS  Google Scholar 

  • Morita T, Kubota H, Murata K, Nozaki M, Delarbre C, et al. (1992) Evolution of the mouse t haplotype: recent and worldwide introgression to Mus musculus. Proc Natl Acad Sci USA 89:6851–6855

    Article  PubMed  CAS  Google Scholar 

  • Nagata K (1998) Expression and function of heat shock protein 47: a collagen-specific molecular chaperone in the endoplasmic reticulum. Matrix Biol 16:379–386

    Article  PubMed  CAS  Google Scholar 

  • Nichols WC, Seligsohn U, Zivelin A, Terry VH, Hertel CE, et al. (1998) Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII. Cell 93:61–70

    Article  PubMed  CAS  Google Scholar 

  • Olivecrona T, Chernick SS, Bengtsson-Olivecrona G, Paterniti JR Jr, Brown WV, et al. (1985) Combined lipase deficiency (cld/cld) in mice. Demonstration that an inactive form of lipoprotein lipase is synthesized. J Biol Chem 260:2552–2557

    PubMed  CAS  Google Scholar 

  • Paterniti JR Jr, Brown WV, Ginsberg HN, Artzt K (1983) Combined lipase deficiency (cld): a lethal mutation on chromosome 17 of the mouse. Science 221:167–169

    Article  PubMed  CAS  Google Scholar 

  • Perret B, Mabile L, Martinez L, Terce F, Barbaras R, et al. (2002) Hepatic lipase: structure/function relationship, synthesis, and regulation. J Lipid Res 43:1163–1169

    PubMed  CAS  Google Scholar 

  • Peterfy M, Phan J, Reue K (2005) Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis. J Biol Chem 280:32883–32889

    Article  PubMed  CAS  Google Scholar 

  • Reue K, Doolittle MH (1996) Naturally occurring mutations in mice affecting lipid transport and metabolism. J Lipid Res 37:1387–1405

    PubMed  CAS  Google Scholar 

  • Sano Y, Shimada T, Nakashima H, Nicholson RH, Eliason JF, et al. (2001) Random monoallelic expression of three genes clustered within 60 kb of mouse t complex genomic DNA. Genome Res 11:1833–1841

    PubMed  CAS  Google Scholar 

  • Schimenti J (2000) Segregation distortion of mouse t haplotypes the molecular basis emerges. Trends Genet 16:240–243

    Article  PubMed  CAS  Google Scholar 

  • Schroder M, Kaufman RJ (2005) ER stress and the unfolded protein response. Mutat Res 569:29–63

    PubMed  Google Scholar 

  • Scow RO, Schultz CJ, Park JW, Blanchette-Mackie EJ (1998) Combined lipase deficiency (cld/cld) in mice affects differently post-translational processing of lipoprotein lipase, hepatic lipase and pancreatic lipase. Chem Phys Lipids 93:149–155

    Article  PubMed  CAS  Google Scholar 

  • Silver LM (1990) At the crossroads of developmental genetics: the cloning of the classical mouse T locus. Bioessays 12:377–380

    Article  PubMed  CAS  Google Scholar 

  • Silver LM, Artzt K (1981) Recombination suppression of mouse t-haplotypes due to chromatin mismatching. Nature 290:68–70

    Article  PubMed  CAS  Google Scholar 

  • Sutherland HF, Pick E, Francis F, Lehrach H, Frischauf AM (1995) Mapping around the Fused locus on mouse chromosome 17. Mamm Genome 6:449–453

    Article  PubMed  CAS  Google Scholar 

  • Vernet C, Artzt K (1995) Mapping of 12 markers in the proximal region of mouse chromosome 17 using recombinant t haplotypes. Mamm Genome 6:219–221

    Article  PubMed  CAS  Google Scholar 

  • Vernet C, Abe K, Artzt K (1998) Genetic mapping of 10 microsatellites in the t complex region of mouse chromosome 17. Mamm Genome 9:472

    Article  PubMed  CAS  Google Scholar 

  • Walmsley AR, Batten MR, Lad U, Bulleid NJ (1999) Intracellular retention of procollagen within the endoplasmic reticulum is mediated by prolyl 4-hydroxylase. J Biol Chem 274:14884–14892

    Article  PubMed  CAS  Google Scholar 

  • Wong H, Schotz MC (2002) The lipase gene family. J Lipid Res 43:993–999

    Article  PubMed  CAS  Google Scholar 

  • Yeom YI, Abe K, Artzt K (1992) Evolution of the mouse H-2K region: a hot spot of mutation associated with genes transcribed in embryos and/or germ cells. Genetics 130:629–638

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Gail Martin for the kind gift of ES cells carrying the t w18 deletion, and Karen Artzt for sharing DNA from t-haplotype-specific mice. In particular, we are indebted to Karen Artzt for supplying DNA from a recombinant mouse derived from her original elegant studies that first identified the cld mutation, and her many helpful discussions and encouragement over the years. This work was funded by National Institutes of Health grant HL28481 and the Veterans Administration.

Author information

Author notes

  1. Hui Z. Mao

    Present address: Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, 79409, USA

Authors and Affiliations

  1. Department of Medicine, University of California, Los Angeles, Los Angeles, California, 90095, USA

    Miklós Péterfy, Hui Z. Mao & Mark H. Doolittle

  2. Department of Medicine, Greater Los Angeles VA Healthcare Center, Los Angeles, California, 90073, USA

    Miklós Péterfy, Hui Z. Mao & Mark H. Doolittle

  3. Greater Los Angeles VA Healthcare Center, 11301 Wilshire Blvd., Building 113, Room 312, Los Angeles, CA, 90073, USA

    Mark H. Doolittle

Authors
  1. Miklós Péterfy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hui Z. Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark H. Doolittle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark H. Doolittle.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Péterfy, M., Mao, H.Z. & Doolittle, M.H. The cld mutation: narrowing the critical chromosomal region and selecting candidate genes. Mamm Genome 17, 1013–1024 (2006). https://doi.org/10.1007/s00335-006-0045-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-006-0045-3

Keywords

Search

Navigation