Novel and recurrent mutations in the PKD1 (Polycystic Kidney disease) gene

Daniells, C.; Maheshwar, Magitha M.; Lazarou, Lazarus P.; Davies, F.; Coles, Gerry A.; Ravine, David

doi:10.1007/s004390050681

Cited by 34 publications

(27 citation statements)

References 15 publications

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“…Numerous mutations identified in PKD1 and PKD2 have confirmed their role in ADPKD [43][44][45][46][47][48][49]. The majority of mutations in PKD2 are nonsense mutations and result in protein truncation, suggesting that gene inactivation is the main mutational mechanism in PKD2 [45,50].…”

Section: One Hit or Two Mutations In Pkd1 And Pkd2mentioning

confidence: 96%

The polycystins: a novel class of membrane-associated proteins involved in renal cystic disease

Sandford¹,

Mulroy

Foggensteiner

1999

Cellular and Molecular Life Sciences (CMLS)

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Polycystin-1, polycystin-2 and polycystin-L are the predicted protein products of the PKD1, PKD2 and PKDL genes, respectively. Mutations in PKD1 and PKD2 are responsible for almost all cases of autosomal dominant polycystic kidney disease (ADPKD). This condition is one of the commonest mendelian disorders of man with a prevalence of 1:800 and is responsible for nearly 10% of cases of end-stage renal failure in adults. The cloning of PKD1 and PKD2 in recent years has provided the initial steps in defining the mechanisms underlying renal cyst formation in this condition, with the aim of defining pharmacological and genetic interventions that may ameliorate the diverse and often serious clinical manifestations of this disease. The PKD genes share regions of sequence similarity, and all predictintegral membrane proteins. Whilst the predicted protein domain structure of polycystin-1 suggests it is involved in cell-cell or cell-matrix interactions, the similarity of polycystin-2 and polycystin-L to the pore-forming domains of some cation channels suggests that they all form subunits of a large plasma membrane ion channel. In the few years since the cloning of the PKD genes, a consensus that defines the range of mutations, expression pattern, interactions and functional domains of these genes and their protein products is emerging. This review will therefore attempt to summarise these data and provide an insight in to the key areas in which polycystin research is unravelling the mechanisms involved in renal cyst formation.

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Section: One Hit or Two Mutations In Pkd1 And Pkd2mentioning

confidence: 96%

The polycystins: a novel class of membrane-associated proteins involved in renal cystic disease

Sandford¹,

Mulroy

Foggensteiner

1999

Cellular and Molecular Life Sciences (CMLS)

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“…The identity by descent cannot be ruled out for either Q4041X and Q4010X. Both mutations have been identified previously in British patients [112] and then reconfirmed in Australian individuals of British ancestry [115]. Whatever the mechanism of origin, the most common PKD1 mutation known to date, Q4041X, accounts for less than 1% (5 out of 691) of disease alleles.…”

Section: Allelic Heterogeneity Pkd1 Mutationsmentioning

confidence: 99%

“…Comparison of polymorphic haplotypes of the Q4041X-bearing chromosomes in the Italian, British and Spanish families with this mutation revealed no identity by descent. A slipped-mispairing model explaining the recurrence of this mutation was subsequently proposed by Daniells et al [112]. The identity by descent cannot be ruled out for either Q4041X and Q4010X.…”

Section: Allelic Heterogeneity Pkd1 Mutationsmentioning

confidence: 99%

“…When these data are looked upon as a true proportion of all individuals tested (approx. 750 to date) -500 (British, Italian and Spanish) [112], 175 (Spanish) [113], 15 (Cypriots) [114], 41 (Australian and Bulgarian) [115] -only 8% of individuals bear mutations in this region. The sets of data obtained so far suggest that there is no clustering of mutations in the unique part of the PKD1 gene.…”

Section: Allelic Heterogeneity Pkd1 Mutationsmentioning

confidence: 99%

“…Out of the total of 60 mutations identified in the unique part of PKD1 so far, only four, namely Q4041X [112,113,115,117], Q4010X [112,115], R4020X [114,118] and R4227X [116,119], have been reported to occur in more than one family. Comparison of polymorphic haplotypes of the Q4041X-bearing chromosomes in the Italian, British and Spanish families with this mutation revealed no identity by descent.…”

Section: Allelic Heterogeneity Pkd1 Mutationsmentioning

confidence: 99%

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Autosomal Dominant Polycystic Kidney Disease – Clinical and Genetic Aspects

Bogdanova

Markoff²,

Horst³

2002

Kidney Blood Press Res

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Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders in humans. It accounts for 8–10% of the cases of end-stage renal disease worldwide, thus representing a serious medical, economical and social problem. ADPKD is in fact a systemic disorder, characterized with the development of cysts in the ductal organs (mainly the kidneys and the liver), also with gastrointestinal and cardiovascular abnormalities. In the last decade there was significant progress in uncovering the genetic foundations and in understanding of the pathogenic mechanisms leading to the renal impairment. This review will retrace the current knowledge about the epidemiology, pathogenesis, genetics, genetic and clinical heterogeneity, diagnostics and treatment of ADPKD.

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Screening the 3? region of the polycystic kidney disease 1 (PKD1) gene in 41 Bulgarian and Australian kindreds reveals a prevalence of protein truncating mutations

Bogdanova

McCluskey

et al. 2000

Hum. Mutat.

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Screening for disease‐causing mutations in the unique region of the polycystic kidney disease 1 (PKD1) gene was performed in 41 unrelated individuals with autosomal dominant polycystic kidney disease. Exons 34‐41 and 43‐46 were assayed using PCR amplification and SSCP analysis followed by direct sequencing of amplicons presenting variant SSCP patterns. We have identified seven disease‐causing mutations of which five are novel [c.10634‐10656del; c.11587delG; IVS37–10C>A; c.11669‐11674del; c.13069‐13070ins39] and two have been reported previously [Q4010X; Q4041X]. Defects in this part of the gene thus account for 17% of our group of patients. Five of the seven sequence alterations detected are protein‐truncating which is in agreement with mutation screening data for this part of the gene by other groups. The two other mutations are in‐frame deletions or insertions which could destroy important functional properties of polycystin 1. These findings suggest that the first step toward cyst formation in PKD1 patients is the loss of one functional copy of polycystin 1, which indirectly supports the “two‐hit” model of cystogenesis where a second somatic mutation inactivating the normal allele is necessary to occur for development of the disease condition. Hum Mutat 16:166–174, 2000. © 2000 Wiley‐Liss, Inc.

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Novel and recurrent mutations in the PKD1 (Polycystic Kidney disease) gene

Cited by 34 publications

References 15 publications

The polycystins: a novel class of membrane-associated proteins involved in renal cystic disease

The polycystins: a novel class of membrane-associated proteins involved in renal cystic disease

Autosomal Dominant Polycystic Kidney Disease – Clinical and Genetic Aspects

Screening the 3? region of the polycystic kidney disease 1 (PKD1) gene in 41 Bulgarian and Australian kindreds reveals a prevalence of protein truncating mutations

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