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Molecular mechanisms determining severity in patients with Pierson syndrome

Journal of Human Genetics volume 65, pages 355–362 (2020)Cite this article

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Abstract

Null variants in LAMB2 cause Pierson syndrome (PS), a severe congenital nephrotic syndrome with ocular and neurological defects. Patients’ kidney specimens show complete negativity for laminin β2 expression on glomerular basement membrane (GBM). In contrast, missense variants outside the laminin N-terminal (LN) domain in LAMB2 lead to milder phenotypes. However, we experienced cases not showing these typical genotype–phenotype correlations. In this paper, we report six PS patients: four with mild phenotypes and two with severe phenotypes. We conducted molecular studies including protein expression and transcript analyses. The results revealed that three of the four cases with milder phenotypes had missense variants located outside the LN domain and one of the two severe PS cases had a homozygous missense variant located in the LN domain; these variant positions could explain their phenotypes. However, one mild case possessed a splicing site variant (c.3797 + 5G>A) that should be associated with a severe phenotype. Upon transcript analysis, this variant generated some differently sized transcripts, including completely normal transcript, which could have conferred the milder phenotype. In one severe case, we detected the single-nucleotide substitution of c.4616G>A located outside the LN domain, which should be associated with a milder phenotype. However, we detected aberrant splicing caused by the creation of a novel splice site by this single-base substitution. These are novel mechanisms leading to an atypical genotype–phenotype correlation. In addition, all four cases with milder phenotypes showed laminin β2 expression on GBM. We identified novel mechanisms leading to atypical genotype–phenotype correlation in PS.

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Acknowledgements

The authors gratefully acknowledge the cooperation of the attending patients and physicians in this study. The authors also thank Edanz (www.edanzediting.co.jp) for editing the English text of a draft of this manuscript. All phases of this study were supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (subject ID: 17K16087 to SM, 17H04189 to KI, and 19K08726 to KN).

Funding

This study was supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (subject ID: 17K16087 to SM, 17H04189 to KI, and 19K08726 to KN).

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Author notes

  1. These authors contributed equally: Shogo Minamikawa, Saori Miwa

Authors and Affiliations

  1. Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan

    Shogo Minamikawa, Hiroshi Kaito, Takeshi Ninchoji, Tomohiko Yamamura, China Nagano, Nana Sakakibara, Shingo Ishimori, Hiroaki Nagase, Hiroki Takeda, Naoya Morisada, Kazumoto Iijima & Kandai Nozu

  2. Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan

    Saori Miwa & Daishi Hirano

  3. Department of Pediatric Nephrology, Miyagi Children’s Hospital, Sendai, Japan

    Tetsuji Inagaki

  4. Department of Pediatrics, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan

    Kei Nishiyama

  5. Department of Diagnostic Pathology, Kobe City Medical Center General Hospital, Kobe, Japan

    Shigeo Hara

  6. Clinical Research Center, Wakayama Medical University, Wakayama, Japan

    Norishige Yoshikawa

  7. Department of Nephrology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan

    Ryoko Harada & Riku Hamada

  8. Department of Pediatrics, Kita-Harima Medical Center, Ono, Japan

    Natsuki Matsunoshita

  9. Department of Kidney and Vascular Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

    Michio Nagata

  10. Department of Pediatrics, Wakayama Medical University, Wakayama, Japan

    Yuko Shima

  11. Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan

    Koichi Nakanishi

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  1. Shogo Minamikawa
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Correspondence to Kandai Nozu.

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The authors declare that they have no conflict of interest.

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All procedures were reviewed and approved by the Institutional Review Board of Kobe University School of Medicine. Informed consent was obtained from all patients or their parents.

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Minamikawa, S., Miwa, S., Inagaki, T. et al. Molecular mechanisms determining severity in patients with Pierson syndrome. J Hum Genet 65, 355–362 (2020). https://doi.org/10.1038/s10038-019-0715-0

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