Human Genetics

, Volume 138, Issue 1, pp 21–35 | Cite as

Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1–PPP1CB complexes

  • Ikumi Umeki
  • Tetsuya Niihori
  • Taiki Abe
  • Shin-ichiro Kanno
  • Nobuhiko Okamoto
  • Seiji Mizuno
  • Kenji Kurosawa
  • Keisuke Nagasaki
  • Makoto Yoshida
  • Hirofumi Ohashi
  • Shin-ichi Inoue
  • Yoichi Matsubara
  • Ikuma Fujiwara
  • Shigeo Kure
  • Yoko AokiEmail author
Original Investigation


RASopathies are a group of developmental disorders caused by mutations in genes that regulate the RAS/MAPK pathway and include Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome and other related disorders. Whole exome sequencing studies recently identified LZTR1, PPP1CB and MRAS as new causative genes in RASopathies. However, information on the phenotypes of LZTR1 mutation-positive patients and functional properties of the mutations are limited. To identify variants of LZTR1, PPP1CB, and MRAS, we performed a targeted next-generation sequencing and reexamined previously analyzed exome data in 166 patients with suspected RASopathies. We identified eight LZTR1 variants, including a de novo variant, in seven probands who were suspicious for NS and one known de novo PPP1CB variant in a patient with NS. One of the seven probands had two compound heterozygous LZTR1 variants, suggesting autosomal recessive inheritance. All probands with LZTR1 variants had cardiac defects, including hypertrophic cardiomyopathy and atrial septal defect. Five of the seven probands had short stature or intellectual disabilities. Immunoprecipitation of endogenous LZTR1 followed by western blotting showed that LZTR1 bound to the RAF1–PPP1CB complex. Cells transfected with a small interfering RNA against LZTR1 exhibited decreased levels of RAF1 phosphorylated at Ser259. These are the first results to demonstrate LZTR1 in association with the RAF1–PPP1CB complex as a component of the RAS/MAPK pathway.



The authors thank the patients, their family members, and the doctors who participated in this study. We are grateful to Jun-ichi Miyazaki of Osaka University for supplying the pCAGGS expression vector. We thank Daiju Oba, Ayumi Nishiyama, Shingo Takahara, Aya Shibui-Inoue, Yu Katata and Koki Nagai who contributed to the routine diagnostic work, and Yoko Tateda, Kumi Kato, and Riyo Takahashi for their technical assistance.


This study was supported in part by the Grants-in-Aid by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development, AMED to Y.A. (18ek0109241h0002), and the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers 17H04223 to Y.A. and 18K15657 to T.A.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

439_2018_1951_MOESM1_ESM.docx (50 kb)
Supplementary material 1 (DOCX 49 KB)
439_2018_1951_MOESM2_ESM.pdf (2 mb)
Supplementary material 2 (PDF 2060 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ikumi Umeki
    • 1
  • Tetsuya Niihori
    • 1
  • Taiki Abe
    • 1
  • Shin-ichiro Kanno
    • 2
  • Nobuhiko Okamoto
    • 3
  • Seiji Mizuno
    • 4
  • Kenji Kurosawa
    • 5
  • Keisuke Nagasaki
    • 6
  • Makoto Yoshida
    • 7
  • Hirofumi Ohashi
    • 8
  • Shin-ichi Inoue
    • 1
  • Yoichi Matsubara
    • 9
  • Ikuma Fujiwara
    • 10
  • Shigeo Kure
    • 11
  • Yoko Aoki
    • 1
    Email author
  1. 1.Department of Medical GeneticsTohoku University School of MedicineSendaiJapan
  2. 2.Division of Dynamic Proteome in Cancer and Aging, Institute of Development, Aging and CancerTohoku UniversitySendaiJapan
  3. 3.Department of Medical GeneticsOsaka Women’s and Children’s HospitalIzumiJapan
  4. 4.Department of Pediatrics, Central HospitalAichi Human Service CenterKasugaiJapan
  5. 5.Division of Medical GeneticsKanagawa Children’s Medical CenterYokohamaJapan
  6. 6.Division of Pediatrics, Department of Homeostatic Regulation and DevelopmentNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
  7. 7.Department of PediatricsSano Kosei General HospitalSanoJapan
  8. 8.Division of Medical GeneticsSaitama Children’s Medical CenterSaitamaJapan
  9. 9.National Research Institute for Child Health and DevelopmentTokyoJapan
  10. 10.Department of Pediatric Endocrinology and Environmental MedicineTohoku University Graduate School of MedicineSendaiJapan
  11. 11.Department of PediatricsTohoku University School of MedicineSendaiJapan

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