Mutational analysis of PHEX, FGF23 and DMP1 in a cohort of patients with hypophosphatemic rickets

Abstract

Summary Background X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets and autosomal recessive hypophosphatemic rickets make up a group of renal phosphate wasting disorders with common clinical and biochemical characteristics. These three types of rickets are related to mutations in PHEX, FGF23 and DMP1, respectively. Objective The objective of the study was to evaluate the frequency of mutations that occur in these three genes associated with hypophosphatemic rickets. Patients and Methods In this study, we sequenced these genes in 76 members of 46 kindreds from a large hypophosphatemic rickets cohort. Results Forty two individuals from 27 kindreds were found to have mutations in PHEX, 16 of which were novel. One subject had an FGF23 mutation. No individuals were found to have mutations in DMP1 consistent with the presence of recessive hypophosphatemic rickets. Conclusions Our data highlight the wide spectrum of genetic variation that can be seen in PHEX, FGF23 and DMP1 when screening a large cohort with hypophosphatemic rickets.

Mutational analysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets

“…The overall median detection rate of gene mutations reported in previous studies comprising 15 or more HR probands was 66% (range 43-100%), 20,[27][28][29][30][31][32][37][38][39][40][41] in familial probands 66% (44-100%), and in sporadic probands the detection rate was 50% (29-100%). 20,[27][28][29][30]32,37,38 In our study, the MLPA analysis added three PHEX mutations not identified by PCR, dHPLC or sequencing, thus increasing our overall detection rate from 78 to 88%, in familial probands from 67 to 83% and in sporadic probands from 83 to 92%. Our high detection rate of gene mutations, especially among the sporadic patients, may also be due to the robust inclusion/ exclusion criteria of this study.…”

“…We determined a mutation to be disease causing: (1) when the mutation was previously described in the PHEXdb (accessed April, 2012) or characterised in publications, but not yet appearing in the PHEXdb; [20][21][22][23] (2) when the mutation identified was present in all family members with clinically and biochemically verified HR, but not in any of the asymptomatic family members; and/or (3) when the mutation type was predicted to cause a nonfunctional protein as frameshift, deletion, duplication, nonsense or abnormal splicing. Missense mutations were initially tested by the prediction software PolyPhen ('polymorphism phenotyping' , http://genetics.bwh.harvard.edu/pph/) and SIFT ('sorting intolerant from tolerant' , http://sift.jcvi.org/) to predict the impact of missense mutations on protein structure and function based on sequence alignments.…”

Clinical, hormonal, biochemical and genetic characteristics of 75 patients with hypophosphatemic rickets

“…По данным зарубежных исследований [15][16][17][18][19][20], в больших когортах пациентов с ГФР поломки гена PHEX определяются в 50-80% случаев. С. Gaucher и соавт.…”

“…В литературе имеется описание пациентов с со-четанием дефектов гена PHEX с мутациями в генах DMP1, FGF23 [19]. Среди пациентов нашей когорты только у одного выявлена гемизиготная мутация в гене PHEX (p.I174fs) и гетерозиготная мутация в гене DMP1 (р.Q159K), которая была ранее описана [19].…”

“…Среди пациентов нашей когорты только у одного выявлена гемизиготная мутация в гене PHEX (p.I174fs) и гетерозиготная мутация в гене DMP1 (р.Q159K), которая была ранее описана [19]. Моноаллельная замена р.Q159K в гене DMP1 по предикторам базы данных ANNOVAR аннотиро-вана как «условно патогенная» и, вероятнее всего, не влияет на развитие заболевания.…”