Human Genetics

, Volume 127, Issue 3, pp 325–336 | Cite as

Examination of FGFRL1 as a candidate gene for diaphragmatic defects at chromosome 4p16.3 shows that Fgfrl1 null mice have reduced expression of Tpm3, sarcomere genes and Lrtm1 in the diaphragm

  • Nelson LopezJimenez
  • Simon Gerber
  • Vlad Popovici
  • Sonia Mirza
  • Kirsten Copren
  • Linda Ta
  • Gary M. Shaw
  • Beat Trueb
  • Anne M. SlavotinekEmail author
Original Investigation


Fgfrl1 (also known as Fgfr5; OMIM 605830) homozygous null mice have thin, amuscular diaphragms and die at birth because of diaphragm hypoplasia. FGFRL1 is located at 4p16.3, and this chromosome region can be deleted in patients with congenital diaphragmatic hernia (CDH). We examined FGFRL1 as a candidate gene for the diaphragmatic defects associated with 4p16.3 deletions and re-sequenced this gene in 54 patients with CDH. We confirmed six known coding single nucleotide polymorphisms (SNPs): c.209G > A (p.Pro20Pro), c.977G > A (p.Pro276Pro), c.1040T > C (p.Asp297Asp), c.1234C > A (p.Pro362Gln), c.1420G > T (p.Arg424Leu), and c.1540C > T (p.Pro464Leu), but we did not identify any gene mutations. We genotyped additional CDH patients for four of these six SNPs, including the three non-synonymous SNPs, to make a total of 200 chromosomes, and found that the allele frequency for the four SNPs, did not differ significantly between patients and normal controls (p ≥ 0.05). We then used Affymetrix Genechip® Mouse Gene 1.0 ST arrays and found eight genes with significantly reduced expression levels in the diaphragms of Fgfrl1 homozygous null mice when compared with wildtype mice—Tpm3, Fgfrl1 (p = 0.004), Myl2, Lrtm1, Myh4, Myl3, Myh7 and Hephl1. Lrtm1 is closely related to Slit3, a protein associated with herniation of the central tendon of the diaphragm in mice. The Slit proteins are known to regulate axon branching and cell migration, and inhibition of Slit3 reduces cell motility and decreases the expression of Rac and Cdc42, two genes that are essential for myoblast fusion. Further studies to determine if Lrtm1 has a similar function to Slit3 and if reduced Fgfrl1 expression can cause diaphragm hypoplasia through a mechanism involving decreased myoblast motility and/or myoblast fusion, seem indicated.


Congenital Diaphragmatic Hernia Congenital Diaphragmatic Hernia Wildtype Mouse Diaphragmatic Defect Myoblast Fusion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Anne Slavotinek was generously funded by a K08 grant HD053476-01A1 from the National Institute of Child Health and Development (NICHD) at the National Institutes of Health. Dr Beat Trueb was supported by a Swiss National Science Foundation grant, 3100A0-113806. We are grateful to the Genome Analysis Core Facility and the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, for their help with the RT-PCR experiments. This publication was supported by NIH/NCRR UCSF-CTSI Grant Number UL1 RR024131. The findings and conclusions in this report are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the California Department of Public of Health. We thank the California Department of Public Health Maternal Child and Adolescent Health Division for providing data for these analyses.

Supplementary material

439_2009_777_MOESM1_ESM.xls (22 kb)
Supplementary material 1 (XLS 22 kb)


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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Nelson LopezJimenez
    • 1
  • Simon Gerber
    • 2
  • Vlad Popovici
    • 3
  • Sonia Mirza
    • 4
  • Kirsten Copren
    • 4
  • Linda Ta
    • 5
  • Gary M. Shaw
    • 6
  • Beat Trueb
    • 2
  • Anne M. Slavotinek
    • 1
    Email author
  1. 1.Division of Genetics, Department of PediatricsUniversity of CaliforniaSan FranciscoUSA
  2. 2.Department of Clinical ResearchUniversity of BernBernSwitzerland
  3. 3.Swiss Institute of BioinformaticsUniversity of LausanneLausanneSwitzerland
  4. 4.Genome Analysis Core Facility, Helen Diller Family Comprehensive Cancer CenterUniversity of CaliforniaSan FranciscoUSA
  5. 5.Genomics CoreThe J. David Gladstone InstitutesSan FranciscoUSA
  6. 6.Department of PediatricsStanford University School of MedicineStanfordUSA

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