Early and Severe Polycystic Kidney Disease and Related Ciliopathies: An Emerging Field of Interest

Bergmann, Carsten

doi:10.1159/000493532

Cited by 48 publications

(51 citation statements)

References 62 publications

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“…Failure to detect mutations in two unrelated probands using Sanger screening approach may be explained by the heterogeneity of the ARPKD disease where mutations in other recessive cystogenes that phenocopy ARPKD might occur. It is also worth mentioning that none of the unsolved patients have family history of disease, which may be due to mutation in autosomal recessive genes that lead to ARPKD-like phenotypes such as the DZIP1L [8] or even in dominant cystic kidney disease genes such as HNF1B, PKD1 and PKD2 that often occur de novo [17]. Whole exome sequencing approaches that would allow inclusion of genes such as DZIP1L are the suggested option for these unsolved patients.…”

Section: Discussionmentioning

confidence: 99%

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Clinical and Genetic Characteristics of Autosomal Recessive Polycystic Kidney Disease in Oman

Alawi

Molinari

Salmi³

et al. 2020

Preprint

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Background There is a high prevalence of rare genetic disorders in the Middle East, and their study provides unique clinical and genetic insights. Autosomal recessive polycystic kidney disease (ARPKD) is one of the leading causes of kidney and liver-associated morbidity and mortality in Oman. We describe the clinical and genetic profile of cohort of ARPKD patients.Methods We studied patients with a clinical diagnosis of ARPKD ( n =40) and their relatives [parents ( n =24) and unaffected siblings ( n =10)] from 32 apparently unrelated families, who were referred to the National Genetic Centre in Oman between January 2015 and December 2018. Genetic analysis of PKHD1 was performed through next generation sequencing (NGS) and Sanger sequencing.Results A clinical diagnosis of ARPKD was made prenatally in 8 patients, 21 were diagnosed during infancy (0-1 year), 9 during early childhood (2-8 years) and 2 at later ages (9-13 years). Clinical phenotypes included polycystic kidneys, hypertension, hepatic fibrosis and splenomegaly. 24 patients had documented chronic kidney disease. 24 out of the 32 families had a family history suggesting an autosomal recessive pattern of inherited kidney disease, and there was known consanguinity in 21 families (66%). A molecular genetic diagnosis with biallelic PKHD1 mutations was confirmed in 38 patients from 30 different families, giving a detection rate of 94%. Two unrelated patients remained genetically unsolved. In all of the solved cases, only four different PKHD1 missense pathogenic variants were identified: c.107C>T, p.(Thr36Met); c.406A>G, p.(Thr136Ala); c.4870C>T, p.(Arg1624Trp) and c.9370C>T, p.(His3124Tyr) located in exons 3, 6, 32 and 58, respectively. The c.406A>G, p.(Thr136Ala) missense mutation was detected homozygously in one family and heterozygously with a c.107C>T, p.(Thr36Met) allele in 5 other families. Overall, the most commonly detected pathogenic allele was c.107C>T; (Thr36Met), which was seen in 24 families.Conclusion Molecular genetic screening of PKHD1 in clinically suspected ARPKD cases produced a high diagnostic rate. The four PKHD1 missense variants identified suggest there may be common founder alleles in the Omani population. Cost effective targeted PCR analysis of these specific alleles can be a useful diagnostic tool for future cases of suspected ARPKD in Oman.

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Section: Discussionmentioning

confidence: 99%

“…However, evidence is accumulating on the increased pathogenicity of some missense mutations that may cause complete loss of function effects [15]. The wide variability in ARPKD severity among patients may in part be explained by differences in PKHD1 mutations, influences of modifiers genes and environmental factors [17].…”

Section: Discussionmentioning

confidence: 99%

Clinical and Genetic Characteristics of Autosomal Recessive Polycystic Kidney Disease in Oman

Alawi

Molinari

Salmi³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Failure to detect mutations in two unrelated probands using the Sanger screening approach alone may be explained by the heterogeneity of the ARPKD disease where mutations may lay in other exons or indeed in other recessive cystogenes that phenocopy ARPKD. None of the unsolved patients had have family history of kidney disease, therefore mutations in autosomal recessive genes that lead to ARPKD-like phenotypes such as the DZIP1L [8] or even in dominant cystic kidney disease genes such as HNF1B, PKD1 and PKD2 that often occur de novo are possible [17]. Whole exome sequencing approaches that would allow inclusion of genes such as DZIP1L are the suggested option for these unsolved patients.…”

Section: Discussionmentioning

confidence: 99%

“…However, evidence is accumulating on the increased pathogenicity of some missense mutations that may cause complete loss of function effects [15]. The wide variability in ARPKD severity among patients may in part be explained by differences in PKHD1 mutations, in uences of modi ers genes and environmental factors [17].…”

Section: Discussionmentioning

confidence: 99%

Clinical and Genetic Characteristics of Autosomal Recessive Polycystic Kidney Disease in Oman

Alawi

Molinari

Salmi³

et al. 2020

Preprint

View full text Add to dashboard Cite

Introduction There is a high prevalence of rare genetic disorders in the Middle East, and their study provides unique clinical and genetic insights. Autosomal recessive polycystic kidney disease (ARPKD) is one of the leading causes of kidney and liver-associated morbidity and mortality in Oman. We describe the clinical and genetic profile of cohort of ARPKD patients. Methods We studied patients with a clinical diagnosis of ARPKD ( n =40) and their relatives [parents ( n =24) and unaffected siblings ( n =10)] from 32 apparently unrelated families, who were referred to the National Genetic Centre in Oman between January 2015 and December 2018. Genetic analysis of PKHD1 was performed through next generation sequencing (NGS) and Sanger sequencing. Results A clinical diagnosis of ARPKD was made prenatally in 8 patients, 21 were diagnosed during infancy (0-1 year), 9 during early childhood (2-8 years) and 2 at later ages (9-13 years). Clinical phenotypes included polycystic kidneys, hypertension, hepatic fibrosis and splenomegaly. 24 patients had documented chronic kidney disease. 24 out of the 32 families had a family history suggesting an autosomal recessive pattern of inherited kidney disease, and there was known consanguinity in 21 families (66%). A molecular genetic diagnosis with biallelic PKHD1 mutations was confirmed in 38 patients from 30 different families, giving a detection rate of 94%. Two unrelated patients remained genetically unsolved. In all of the solved cases, only four different PKHD1 missense pathogenic variants were identified: c.107C>T, p.(Thr36Met); c.406A>G, p.(Thr136Ala); c.4870C>T, p.(Arg1624Trp) and c.9370C>T, p.(His3124Tyr) located in exons 3, 6, 32 and 58, respectively. The c.406A>G, p.(Thr136Ala) missense mutation was detected homozygously in one family and heterozygously with a c.107C>T, p.(Thr36Met) allele in 5 other families. Overall, the most commonly detected pathogenic allele was c.107C>T; (Thr36Met), which was seen in 24 families. Conclusion Molecular genetic screening of PKHD1 in clinically suspected ARPKD cases produced a high diagnostic rate. The four PKHD1 missense variants identified suggest there may be common founder alleles in the Omani population. Cost effective targeted PCR analysis of these specific alleles can be a useful diagnostic tool for future cases of suspected ARPKD in Oman.

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“…HNF1B, PKD1, NPHP2, NPHP3, and NPHP13, can phenocopy ARPKD. 7 For reasons yet to be explained, mice with targeted disruption of Pkhd1 exhibit little or no kidney disease. [8][9][10][11][12][13][14][15] In the absence of a Pkhd1 mutant mouse model that accurately recapitulates the human disease phenotype, the cpk mouse carrying a spontaneous truncating mutation in Cys1 has been the most widely studied mouse model of ARPKD.…”

Section: Introductionmentioning

confidence: 99%

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

Yang¹,

O’Connor²,

Kesterson

et al. 2020

Preprint

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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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Early and Severe Polycystic Kidney Disease and Related Ciliopathies: An Emerging Field of Interest

Cited by 48 publications

References 62 publications

Clinical and Genetic Characteristics of Autosomal Recessive Polycystic Kidney Disease in Oman

Clinical and Genetic Characteristics of Autosomal Recessive Polycystic Kidney Disease in Oman

Clinical and Genetic Characteristics of Autosomal Recessive Polycystic Kidney Disease in Oman

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

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