title: 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.
abstract: Heritable forms of hypophosphatemic rickets (HR) include X-linked dominant (XLH), autosomal recessive, and autosomal dominant HR (from deactivating mutations in PHEX, DMP1 or ENPP1, and activating mutations in FGF23, 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 PHEX mutations. However, the remaining 19 lacked readily identifiable defects in PHEX, DMP1, or FGF23. In 2008, a novel single-base change near the polyadenylation (pA) signal in the 3'-UTR of PHEX was identified in XLH by other investigators. This c.*231A > G mutation is 3-bp upstream of the putative pA signal (AATAAA) in PHEX. 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 PHEX 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 (p = 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, PHEX c.*231A > G can masquerade as sporadic or X-linked recessive HR.
authors.affiliation: Division of Bone and Mineral Diseases, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA; Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Mumm
authors.forename: Margaret
authors.initials: M
authors.lastname: Huskey
authors.forename: Adela
authors.initials: A
authors.lastname: Cajic
authors.forename: Valerie
authors.initials: V
authors.lastname: Wollberg
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Madson
authors.forename: Deborah
authors.initials: D
authors.lastname: Wenkert
authors.forename: William H
authors.initials: WH
authors.lastname: McAlister
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gottesman
authors.forename: Michael P
authors.initials: MP
authors.lastname: Whyte
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D053098:Familial Hypophosphatemic Rickets / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics*; D005260:Female; D000089703:Fibroblast Growth Factor-23; D006801:Humans; D007223:Infant; D008297:Male; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000235:genetics*; D017354:Point Mutation; D039104:RNA 3' Polyadenylation Signals / Q000235:genetics*; D011859:Radiography
chemical_list: D020413:3' Untranslated Regions; C000717427:FGF23 protein, human; D000089703:Fibroblast Growth Factor-23; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human
keywords: AND RICKETS; DISORDERS OF CALCIUM/PHOSPHATE METABOLISM; GENETIC RESEARCH; OSTEOMALACIA