Functional analysis of 22 splice-site mutations in the PHEX, the causative gene in X-linked dominant hypophosphatemic rickets

BinEssa, Huda A.; Zou, Minjing; Al-Enezi, Anwar F; Alomrani, Basma; Al-Faham, Manar S A; Al-Rijjal, Roua A.; Meyer, Brian F.; Shi, Yufei

doi:10.1016/j.bone.2019.05.017

“…XLH is a dominant disorder and the most common form of heritable rickets, and inactive mutations in PHEX have been implicated in the pathogenesis of XLH. In accordance with the present results, splice-site mutations have been shown to be responsible for 17% of all reported PHEX mutations 5 . Other mutations have also been reported in the splice acceptor site of intron 17 2,6,7 .…”

supporting

confidence: 93%

Phenotypes of a family with XLH with a novel PHEX mutation

Yamamoto

¹

,

Nakamura

²

,

Ohata

³

et al. 2020

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X-linked hypophosphatemia (XLH) is the most common form of heritable hypophosphatemic rickets. We encountered a 4-year-old boy with a novel variant in the phosphate-regulating neutral endopeptidase homolog X-linked (PHEX) gene who presented with a short stature, genu valgum, and scaphocephaly. The same mutation was identified in his mother and sister; however, the patient presented with a more severe case.

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“…Pathogenic variants affecting +5 position of the donor splice site have been reported in other genes 51 including the OXCT1 gene in succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency 52 and the gene encoding fumarylacetoacetate hydrolase in hereditary tyrosinaemia 53 . Detailed analysis of G-to-A sequence changes at the +5 position have revealed disrupted base pairing between donor splice site of a pre-mRNA and the U1snRNP of the spliceosome leading to decreased efficiency of the splice site recognition and exon skipping that can result in frameshifting and premature protein termination 54 . However, this ex vivo system does not allow us to predict whether the variant leads to structural protein alterations (e.g.…”

Section: Discussionmentioning

confidence: 99%

Cystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered Myc expression

Yang¹,

Harafuji²,

O’Connor³

et al. 2021

Sci Rep

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Mutation of the Cys1 gene underlies the renal cystic disease in the Cys1cpk/cpk (cpk) mouse that phenocopies human autosomal recessive polycystic kidney disease (ARPKD). Cystin, the protein product of Cys1, is expressed in the primary apical cilia of renal ductal epithelial cells. In previous studies, we showed that cystin regulates Myc expression via interaction with the tumor suppressor, necdin. Here, we demonstrate rescue of the cpk renal phenotype by kidney-specific expression of a cystin-GFP fusion protein encoded by a transgene integrated into the Rosa26 locus. In addition, we show that expression of the cystin-GFP fusion protein in collecting duct cells down-regulates expression of Myc in cpk kidneys. Finally, we report the first human patient with an ARPKD phenotype due to homozygosity for a deleterious splicing variant in CYS1. These findings suggest that mutations in Cys1/CYS1 cause an ARPKD phenotype in mouse and human, respectively, and that the renal cystic phenotype in the mouse is driven by overexpression of the Myc proto-oncogene.

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“…Pathogenic variants affecting +5 position of the donor splice site have been reported in other genes [47][48][49] and detailed analysis of G-to-A sequence changes at the +5 position have revealed disrupted base pairing between donor splice site of a pre-mRNA and the U1snRNP of the spliceosome leading to decreased efficiency of the splice site recognition and exon skipping. 50 The identification of a pathogenic CYS1 variant in a patient with an ARPKD-like phenotype confirms the importance of the CYS1 gene product for normal function of human collecting duct cells. While it is surprising that CYS1 deficiency causing ARPKD has been observed in only one family, it is important to note that this gene is GC-rich, particularly its first exon ( Figure S3).…”

Section: Discussionmentioning

confidence: 59%

Cystin gene mutations cause autosomal recessive polycystic kidney disease associated with alteredMycexpression

Yang¹,

O’Connor²,

Kesterson

³

et al. 2020

Preprint

0

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Mutation of the Cys1 gene underlies the renal cystic disease in the Cys1 cpk/cpk (cpk) mouse that phenocopies human autosomal recessive polycystic kidney disease (ARPKD). Cystin, the protein product of Cys1, is expressed in the primary apical cilia of renal ductal epithelial cells. In previous studies, we showed that cystin regulates Myc expression via interaction with the tumor suppressor, necdin. Here, we demonstrate rescue of the cpk renal phenotype by kidney-specific expression of a cystin-GFP fusion protein encoded by a transgene integrated into the Rosa26 locus. In addition, we show that expression of the cystin-GFP fusion protein in collecting duct cells downregulates expression of Myc in cpk kidneys. Finally, we report the first human patient with an ARPKD phenotype due to homozygosity for a predicted deleterious splicing defect in CYS1.These findings suggest that mutations in the Cys1 mouse and CYS1 human orthologues cause an ARPKD phenotype that is driven by overexpression of the Myc proto-oncogene. Translational Statement:The cystin-deficient cpk mouse is a model for the study of autosomal recessive polycystic kidney disease (ARPKD). We show that the cpk mouse phenotype is associated with altered Myc expression. To date, the clinical relevance of cystin deficiency to human disease was unclear, due to the absence of ARPKD cases associated with CYS1 mutations. We report the first case of ARPKD linked to a CYS1 mutation disrupting normal splicing. These findings confirm the relevance of cystin deficiency to human ARPKD, implicate Myc in disease initiation or progression, and validate the cpk mouse as a translationally relevant disease model.

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Functional analysis of 22 splice-site mutations in the PHEX, the causative gene in X-linked dominant hypophosphatemic rickets

Cited by 22 publications

References 39 publications

Phenotypes of a family with XLH with a novel PHEX mutation

Phenotypes of a family with XLH with a novel PHEX mutation

Cystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered Myc expression

Cystin gene mutations cause autosomal recessive polycystic kidney disease associated with alteredMycexpression

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