Mutational analysis of PHEX, FGF23 and CLCN5 in patients with hypophosphataemic rickets

Güven, Ayla; Al-Rijjal, Roua A.; BinEssa, Huda A.; Doğan, Durmuş; Kör, Yılmaz; Zou, Minjing; Kaya, Namik; Al-Enezi, Anwar F; Hancılı, Suna; Tarım, Ömer; Baitei, Essa Y.; Kattan, Walaa E; Meyer, Brian F.; Shi, Yufei

doi:10.1111/cen.13347

Cited by 23 publications

(21 citation statements)

References 31 publications

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“…More than 220 CLCN5 pathogenic mutations have been reported so far. Mutations were found scattered along all exons of the gene and in different protein domains [9,[34][35][36][37][38][39][40][41][42][43][44][45]. Mansour-Hendili et al [9] reported that the majority were missense and frameshift mutations (33.33% and 29.05% respectively) followed by nonsense mutations (17.52%), splicing mutations (12.39%), and large deletions (4.70%).…”

Section: Discussionmentioning

confidence: 99%

Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies

Gianesello

Ceol

Bertoldi

et al. 2020

IJMS

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Dent disease (DD), an X-linked renal tubulopathy, is mainly caused by loss-of-function mutations in CLCN5 (DD1) and OCRL genes. CLCN5 encodes the ClC-5 antiporter that in proximal tubules (PT) participates in the receptor-mediated endocytosis of low molecular weight proteins. Few studies have analyzed the PT expression of ClC-5 and of megalin and cubilin receptors in DD1 kidney biopsies. About 25% of DD cases lack mutations in either CLCN5 or OCRL genes (DD3), and no other disease genes have been discovered so far. Sanger sequencing was used for CLCN5 gene analysis in 158 unrelated males clinically suspected of having DD. The tubular expression of ClC-5, megalin, and cubilin was assessed by immunolabeling in 10 DD1 kidney biopsies. Whole exome sequencing (WES) was performed in eight DD3 patients. Twenty-three novel CLCN5 mutations were identified. ClC-5, megalin, and cubilin were significantly lower in DD1 than in control biopsies. The tubular expression of ClC-5 when detected was irrespective of the type of mutation. In four DD3 patients, WES revealed 12 potentially pathogenic variants in three novel genes (SLC17A1, SLC9A3, and PDZK1), and in three genes known to be associated with monogenic forms of renal proximal tubulopathies (SLC3A, LRP2, and CUBN). The supposed third Dent disease-causing gene was not discovered.

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Section: Discussionmentioning

confidence: 99%

Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies

Gianesello

Ceol

Bertoldi

et al. 2020

IJMS

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“…The diagnosis of XLH is based on the association of clinical, radiological and biochemical findings (Box 1). In patients with a negative family history (approximately one-third of reported patients 31,32 ), mutational analysis of the PHEX gene is recommended, which can provide negative or positive confirmation in ~70-90% of cases 31,[33][34][35][36][37][38][39][40][41][42][43] . Specific molecular genetic defects such as large deletions, deletions removing pseudo-exons of PHEX or mosaicism can be difficult to identify 44,45 .…”

Section: Harrison's Groovementioning

confidence: 99%

Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia

et al. 2019

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X-linked hypophosphataemia (XLH) is an X-linked dominant disorder caused by mutations in PHEX (located at Xp22.1), which encodes a cell-surface-bound protein-cleavage enzyme (phosphate-regulating neutral endopeptidase PHEX), predominantly expressed in osteoblasts, osteocytes and teeth (odontoblasts and cementoblasts). XLH is the most common cause of inherited phosphate wasting, with an incidence of 3.9 per 100,000 live births and a prevalence ranging from 1.7 per 100,000 children to 4.8 per 100,000 persons (children and adults) 1-3. Although the pathogenesis of XLH is not fully understood, animal studies indicate that loss of Phex function results in enhanced secretion of the phosphaturic hormone fibroblast growth factor 23 (FGF23), with osteocytes being the primary source of FGF23 production 4. These effects explain most of the characteristic features of the disease, including renal phosphate wasting with consequent hypophosphataemia, diminished synthesis of active vitamin D (1,25(OH) 2 vitamin D), rickets, osteomalacia, odontomalacia and disproportionate short stature 4-6. Patients usually develop clinical symptoms during the first or second year of life. Early treatment with oral phosphate supplementation and active vitamin D heals rickets, limits dental abscess formation and prevents progressive growth failure, but in a substantial proportion of patients treatment is unsuccessful and/or associated with adverse effects (for example, hyper parathyroidism and nephrocalcinosis) 7,8. Up to two-thirds of children with XLH require lower limb surgery 9-12. Conventional therapy further stimulates FGF23 levels and thereby renal phosphate wasting, resulting in a vicious circle, which might limit its efficacy 6,13-15. Adult patients with XLH are at risk of complications such as early osteoarthritis, enthesopathies, spinal stenosis, pseudofractures and hearing loss, which might limit quality of life 16-18. In 2018, burosumab, a fully human monoclonal IgG1 antibody neutralizing FGF23, was approved by health authorities for the treatment of patients with

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“…These mutations affect the production of the α1/α2 chains of type 1 collagen, an important structural component of the bone, skin, tendons, ligaments, and other connective tissues [44]. Animal studies have also observed muscle weakness in OI mice [45], providing additional evidence for the muscle abnormalities in OI. The exact mechanisms leading to muscle weakness are yet unclear but they can be result of intrinsic muscle factors or direct paracrine effects of the abnormal bone matrix (i.e., increased TGF-β signaling in OI decreases lean mass).…”

Section: Human and Animal Bone-focused Knock-out “Models” Comprising mentioning

confidence: 99%

Genetics of Bone and Muscle Interactions in Humans

Trajanoska

Rivadeneira

Kiel

et al. 2019

Curr Osteoporos Rep

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Purpose of ReviewTo summarize the evidence from recent studies on the shared genetics between bone and muscle in humans.Recent FindingsGenome-wide association studies (GWAS) have successfully identified a multitude of loci influencing the variability of different bone or muscle parameters, with multiple loci overlapping between the traits. In addition, joint analyses of multiple correlated musculoskeletal traits (i.e., multivariate GWAS) have underscored several genes with possible pleiotropic effects on both bone and muscle including MEF2C and SREBF1. Notably, several of the proposed pleiotropic genes have been validated using human cells or animal models.SummaryIt is clear that the study of pleiotropy may provide novel insights into disease pathophysiology potentially leading to the identification of new treatment strategies that simultaneously prevent or treat both osteoporosis and sarcopenia. However, the role of muscle factors (myokines) that stimulate bone metabolism, as well as osteokines that affect muscles, is in its earliest stage of understanding.

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Mutational analysis of PHEX, FGF23 and CLCN5 in patients with hypophosphataemic rickets

Cited by 23 publications

References 31 publications

Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies

Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies

Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia

Genetics of Bone and Muscle Interactions in Humans

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