Seven novel and six de novo PHEX gene mutations in patients with hypophosphatemic rickets

Abstract

Inactivating mutations in phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX) have been identified as a cause of X-linked hypophosphatemic rickets (XLH; OMIM 307800). In the present study, we enrolled 43 patients from 18 unrelated families clinically diagnosed with hypophosphatemic rickets and 250 healthy controls. For each available individual, all 22 exons with their exon-intron boundaries of the PHEX gene were directly sequenced. The levels of serum fibroblast growth factor 23 (FGF23) were measured as well. Sequencing analysis detected 17 different PHEX gene mutations, and 7 of these were identified as novel: 3 missense mutations, including c.304G>A (p.Gly102Arg) in exon 3, c.229T>C (p.Cys77Arg) in exon 3 and c.824T>C (p.Leu275Pro) in exon 7; 2 deletion mutations, including c.528delT (p.Glu177LysfsX44) in exon 5 and c.1234delA (p.Ser412ValfsX12) in exon 11; and 2 alternative splicing mutations, including c.436_436+1delAG in intron 4 at splicing donor sites and c.1483-1G>C in intron 13 at splicing acceptor sites. Moreover, 6 mutations were proven to be de novo in 6 sporadic cases and the probands were all females. No mutations were found in the 250 healthy controls. The serum levels of FGF23 varied widely among the patients with XLH, and no significant difference was found when compared with those of the healthy controls. On the whole, the findings of this study provide new insight into the spectrum of PHEX mutations and provide potential evidence of a critical domain in PHEX protein. In addition, the finding of an overlap of the serum FGF23 levels between the patients with XLH and the healthy controls indicates its limited diagnostic value in XLH.

Rare, genetically conditioned forms of rickets: Differential diagnosis and advances in diagnostics and treatment

“…18 PHEX gene mutations are responsible for the occurrence of classic X-linked hypophosphatemic rickets. [18][19][20] They are inherited as dominant, and therefore the acronym X-linked dominant hypophosphatemic rickets (XLDHR) is also used (OMIM #307800); however, some families have also been described where inheritance followed the recessive pattern, which was reflected by asymptomatic disease course in women who were mutation carriers. 21 Other authors question this observation and claim that inheritance does have a dominant pattern but that in women the course of the disease is milder due to the presence of the second copy of the gene, and that, therefore, it may seem asymptomatic but in fact is oligosymptomatic but not adequately diagnosed.…”

<p>PHEX Gene Mutation in a Patient with X-Linked Hypophosphatemic Rickets in a Developing Country</p>

“…1,3,4 It is estimated that XLHR has a prevalence of one in every 20,000 newborns and follows a dominant X-linked inheritance. [5][6][7][8] XLHR is caused by mutations in the PHEX gene; to date, more than 460 mutations associated with this condition have been reported in the literature. 5,9,10 The gene is located in Xp22.1.…”

Molecular and Biochemical Aspects of Hypophosphatemic Rickets; an Updated Review

“…For example, frameshift mutations account for 25% whereas 23% is reported for alternative splicing, other frequencies are as follow: 22% missense, 18% nonsense, 8% deletion and 4% polymorphisms. 11,13,28,55 Mutations mostly affect the protein secondary structure. Exon 7 is the most infrequent mutant exon reported in PHEX database.…”

“…Cysteine residues generate the secondary structure of the protein while zinc-binding sites are necessary for catalytic activity of protein. 55 Loss of function mutation in PHEX gene stimulates FGF23 in bone. There are different types of mutations in PHEX gene including nonsense, deletion, missense, insertion, and mutation in splice site.…”

“…Therefore, this region is assumed to be the most important domain for the function of PHEX and it is associated with more severe symptoms. 55 Splice site mutation like c.1080 A›G leads to the production of mRNA that lacks exon 10 and subsequent loss of zinc-binding motif as well as cysteine residues.…”