PHEX 3′‐UTR c.*231A>G Near The Polyadenylation Signal is a Relatively Common, Mild, American Mutation That Masquerades as Sporadic or X‐Linked Recessive Hypophosphatemic Rickets. (January 2015)

• Record Type: Journal Article
• Authors: Mumm, Steven; Huskey, Margaret; Cajic, Adela; Wollberg, Valerie; Zhang, Fan; Madson, Katherine L; Wenkert, Deborah; McAlister, William H; Gottesman, Gary S; Whyte, Michael P
• Is Part Of: Journal of bone and mineral research. Volume 30:Number 1(2015:Jan.)
• Page Start: 137
• Page End: 143
• Publication Date: 2015-01
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.2307
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="jbmr2307-sec-0001" sec-type="section"> <p>Heritable forms of hypophosphatemic rickets (HR) include X‐linked dominant (XLH), autosomal recessive, and autosomal dominant HR (from deactivating mutations in <italic>PHEX</italic>, <italic>DMP1</italic> or <italic>ENPP1</italic>, and activating mutations in <italic>FGF23</italic>, respectively). Over 30 years, we have cared for 284 children with HR. For those 72 deemed sporadic XLH, we preliminarily reported mutation analysis for 30 subjects. Eleven had <italic>PHEX</italic> mutations. However, the remaining 19 lacked readily identifiable defects in <italic>PHEX</italic>, <italic>DMP1</italic>, or <italic>FGF23</italic>. In 2008, a novel single‐base change near the polyadenylation (pA) signal in the 3′‐UTR of <italic>PHEX</italic> was identified in XLH by other investigators. This c.*231A > G mutation is 3‐bp upstream of the putative pA signal (AATAAA) in <italic>PHEX</italic>. Accordingly, we investigated whether this 3′‐UTR defect accounted for HR in any of these 19 sporadic XLH patients. PCR amplification and sequencing of their 3′‐UTR region showed the c.*231A > G mutation in four unrelated boys. Then, among an additional 22 of our 72 "sporadic" XLH patients, one boy and one girl were found to have the 3′‐UTR defect, totaling six patients. Among these 52 sporadic XLH patients with <italic>PHEX</italic> analysis, 36 were girls and 16 were boys; ie, a ∼2:1 gender ratio consistent with XLH. However, finding five boys and only one girl with this 3′‐UTR mutation presented an unexplained gender bias (<italic>p</italic> = 0.02). Haplotyping for the five boys, all reportedly unrelated, showed a common core haplotype suggesting a founder. Five of their six mothers had been studied clinically and biochemically (three radiologically). Remarkably, the seemingly unaffected mothers of four of these boys carried the 3′‐UTR mutation. These healthy women had normal height, straight limbs, lacked the radiographic presentation of XLH, and showed normal or slight decreases in fasting serum Pi levels and/or TmP/GFR. Hence, <italic>PHEX</italic> c.*231A > G can masquerade as sporadic or X‐linked recessive HR. © 2014 American Society for Bone and Mineral Research.</p> </sec> </abstract>