Hypophosphatemic rickets caused by a novel splice donor site mutation and activation of two cryptic splice donor sites in the PHEX gene

Minjing Zou; Derya Buluş; Roua A. Al-Rijjal; Nesibe Andıran; Huda BinEssa; Walaa E. Kattan; Brian Meyer; Yufei Shi

doi:10.1515/jpem-2014-0103

Article

Hypophosphatemic rickets caused by a novel splice donor site mutation and activation of two cryptic splice donor sites in the PHEX gene

Minjing Zou , Derya Buluş , Roua A. Al-Rijjal , Nesibe Andıran , Huda BinEssa , Walaa E. Kattan , Brian Meyer and Yufei Shi

Published/Copyright: August 5, 2014

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From the journal Journal of Pediatric Endocrinology and Metabolism Volume 28 Issue 1-2

Abstract

X-linked hypophosphatemic rickets (XLH) is the most common inherited form of rickets. XLH is caused by inactivating mutations in the PHEX gene and is transmitted as an X-linked dominant disorder. We investigated PHEX mutation in a sporadic Turkish girl with hypophosphatemic rickets. The patient was 2 years of age with a complaint of inability to walk. She had bowing of legs and growth retardation. Laboratory data showed normal calcium, low phosphate with markedly elevated ALP, and low phosphate renal tubular reabsorption. She was treated with Calcitriol 0.5 mg/kg/day and oral phosphate supplement with good response. The entire coding region of PHEX gene was sequenced from patient’s peripheral leukocyte DNA and a novel 13 bp deletion at the donor splice site of exon5 was found (c.663+12del). Instead of using the donor splice site of intron 4 to splice out exon 5 and intron 5, the spliceosome utilized two nearby cryptic donor splice sites (5′ splice site) to splice out intron 4, resulting in two smaller transcripts. Both of them could not translate into functional proteins due to frameshift. Her parents did not carry the mutation, indicating that this is a de novo PHEX mutation likely resulting from mutagenesis of X chromosome in paternal germ cells. We conclude that c.663+12del is a novel mutation that can activate nearby cryptic 5′ splice sites. The selection of cryptic 5′ splice sites adds the complexity of cell’s splicing mechanisms. The current study extends the database of PHEX mutation and cryptic 5′ splice sites.

Keywords: hypophosphatemic rickets; PHEX mutation; vitamin D; X-linked

Corresponding author: Yufei Shi, MD, Department of Genetics (MBC-03), King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia, E-mail: yufei@kfshrc.edu.sa

aContribute equally to the work.

Acknowledgments

This study was partially funded by a grant from KACST 11-BIO1434-20.

Conflict of interest statement

Authors’ conflict of interest disclosure: All authors have nothing to disclose.

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Received: 2014-2-27

Accepted: 2014-6-19

Published Online: 2014-8-5

Published in Print: 2015-1-1

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Articles in the same Issue

https://doi.org/10.1515/jpem-2014-0103

Keywords for this article

hypophosphatemic rickets; PHEX mutation; vitamin D; X-linked