A Unique Mechanism of a Novel Synonymous PHEX Variant Causing X-Linked Hypophosphatemia

Author:

Alhamoudi Kheloud M1ORCID,Alghamdi Balgees1,Alswailem Meshael1,Nasir Abdul2,Aljomaiah Abeer3,Al-Hindi Hindi4,Alzahrani Ali S13ORCID

Affiliation:

1. Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre , MBC#03, PO BOX 3354, Riyadh, 11211 , Saudi Arabia

2. Department of Molecular science and Technology, Ajou University , Suwon, 443-749 , South Korea

3. Department of Medicine, King Faisal Specialist Hospital & Research Centre , P.O Box 3354, Riyadh 11211 , Saudi Arabia

4. Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital & Research Centre , P.O Box 3354, Riyadh 11211 , Saudi Arabia

Abstract

Abstract Context Synonymous mutations are usually nonpathogenic. Objective We report here a family with X-linked hypophosphatemia (XLH) due to a novel synonymous PHEX variant with a unique mechanism. Methods We studied a 4-member family (a mother, a son, and 2 daughters), all affected with XLH. Genomic DNA was extracted from peripheral leucocytes. Whole exome sequencing (WES) was used to identify the underlying genetic variant in the proband (the son). Sanger sequencing was used to confirm this variant in the proband and his family members. RT-PCR and sequencing of the cDNA revealed the effect of this variant on the PHEX structure and function Results A synonymous variant in the PHEX gene (c.1701A>C) was identified in all affected members. This variant changes the first nucleotide of exon 17 from adenine to cytosine. Using RT-PCR, this variant was shown to interfere with splicing of exons 16 with 17 resulting in a single shorter PHEX transcript in the proband compared to normal control. Sanger sequencing of the cDNA revealed a complete skipping of exon 17 and direct splicing of exons 16 and 18. This led to a frameshift and an introduction of a new stop codon in the next codon (codon 568), which ultimately led to truncation and loss of the final 183 amino acids of PHEX. Conclusion This novel variant shows how a synonymous exonic mutation may induce a complex series of changes in the transcription and translation of the gene and causes a disease, a mechanism that is not commonly recognized.

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

Reference40 articles.

1. A genetic study of familial hypophosphatemia and vitamin D resistant rickets with a review of the literature;Winters;Medicine (Baltim).,1958

2. Mutational analysis and genotype-phenotype correlation of the PHEX gene in X-linked hypophosphatemic rickets;Holm;J Clin Endocrinol Metab.,2001

3. Inherited forms of rickets and osteomalacia;Thakker;Baillieres Clin Endocrinol Metab.,1988

4. Intra-spinal new bone formation and spinal cord compression in familial hypophosphataemic vitamin D resistant osteomalacia;Adams;Q J Med.,1986

5. A clinical and molecular genetic study of hypophosphatemic rickets in children;Cho;Pediatr Res.,2005

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3