Molecular genetic diagnosis of autosomal dominant polycystic kidney disease in a newborn with bilateral cystic kidneys detected prenatally and multiple skeletal malformations.

Turco, Alberto; E, Padovani; Chiaffoni, Gian Paolo; Peissel, Bernard; Rossetti, Sandro; Marcolongo, Alma; Gammaro, Linda; Maschio, Giuseppe; Pignatti, Pier Franco

doi:10.1136/jmg.30.5.419

Cited by 26 publications

(13 citation statements)

References 15 publications

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“…Pediatricians, pediatric nephrologists, and obstetricians are (and will be even more in the future) urged to provide information on possible renal outcome in those cases diagnosed early during pregnancies. However, a t present, postnatal renal evolution in children prenatally diagnosed with ADPKD is not sufficiently well-documented despite the number of published cases [Ceccherini et al, 1989;Fick et al, 1993;Gagnadoux and Habib, 1989;Garel et al, 1982;Journel et al, 1989;Main et al, 1983;McHugo et al, 1988;Novelli et al, 1989;Pretorius et al, 1987;Sedman et al, 1987;Turco et al, 1992;Zerres et al, 19821. We collected prenatal and postnatal US findings and renal function parameters from known prenatally diagnosed patients with ADPKD, including the 3 cases in this report (Table I).…”

Section: Discussionmentioning

confidence: 94%

“…With the widespread use of ultrasound in pregnant women and genetic studies, the number of prenatal diagnoses of autosomal-dominant polycystic kidney disease (ADPKD) has increased [Ceccherini et al, 1989;Fick et al, 1993;Gagnadoux and Habib, 1989;Garel et al, 1982;Journel et al, 1989;Main et al, 1983;McHugo et al, 1988;Novelli et al, 1989;Pretorius et al, 1987;Sedman et al, 1987;Turco et al, 1992;Zerres et al, 0 1996 Wiley-Liss, Inc.…”

Section: Introductionmentioning

confidence: 98%

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Prenatal ultrasonographic findings of dominant polycystic kidney disease and postnatal renal evolution

et al. 1996

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Autosomal dominant polycystic kidney disease (ADPKD) is a relatively common genetic disorder, and its prenatal diagnosis has been reported with increasing frequency. Nevertheless, no data are available on the significance of prenatal ultrasound (US) patterns in predicting postnatal renal function and outcome. We report on one case of ADPKD diagnosed prenatally by US, and on two cases diagnosed immediately after birth, with different prenatal US and renal outcomes. Data on prenatal US findings and postnatal renal evolution are scanty and largely incomplete. Apparently, none of the prenatal findings are consistently different in cases with and without normal postnatal renal function and blood pressure. More complete information on prenatal US findings and postnatal renal evolution is urgently needed. © 1996 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 98%

Prenatal ultrasonographic findings of dominant polycystic kidney disease and postnatal renal evolution

et al. 1996

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“…In addition, there are some very interesting but rare families with early onset of polycystic kidney disease in newborns that are associated with severe skeletal malformations, similar to those observed in mice with homozygous Pkd1 mutations, suggesting that broadly disrupting both alleles in osteoblasts/osteocytes (analogous to the Pkd1 null mouse as opposed to random second hits in ADPKD) might cause clinically apparent bone disease in humans (12,50).…”

Section: Bone From Pkd1mentioning

confidence: 90%

Conditional Disruption of Pkd1 in Osteoblasts Results in Osteopenia Due to Direct Impairment of Bone Formation

Xiao

Zhang

Cao

et al. 2010

Journal of Biological Chemistry

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PC1 (polycystin-1) is a highly conserved, receptor-like multidomain membrane protein widely expressed in various cell types and tissues (1, 2). Mutations of human PKD1 (polycystic kidney disease gene 1) cause autosomal dominant polycystic kidney disease (ADPKD) 2 (3, 4). The genetics of ADPKD is complex, because it is widely held that inactivation of the normal copy of the PKD1 gene by a second somatic mutation in conjunction with the inherited mutation of the other allele is required for renal cyst formation, which occurs in only a subset of the dually affected tubules (5). Although primarily affecting the kidney, ADPKD is also a multisystem disorder (6, 7). Extrarenal manifestations include intracranial and aortic aneurysms and cystic disease of liver and pancreas (8 -11). The biological functions of PC1 are poorly defined in some tissues that express PKD1 transcripts, such as bone. Indeed, the absence of clinically demonstrable skeletal abnormalities in patients with ADPKD initially delayed the investigation of PKD1 function in bone. The apparent lack of abnormalities in other tissues expressing PC1 may arise because of differences in the frequency of a second hit somatic mutation, the presence of other modifying factors that may compensate for lack of PC1 function in other organs (12), or failure to detect more subtle phenotypes. For example, lung was not thought to be affected by PKD1 mutations until computed tomography scans of lungs of ADPKD patients showed a 3-fold increase in the prevalence of bronchiectasis compared with controls (13).Pkd1 is highly expressed in bone, and several mouse models with inactivating mutations of Pkd1 have skeletal abnormalities in the setting of polycystic kidney disease and embryonic lethality (6, 7, 14 -16). Most recently, however, the heterozygous Pkd1 m1Bei mouse, which has an inactivating mutation of Pkd1 and survives to adulthood without polycystic kidney disease, has been shown to develop osteopenia and impaired osteoblastic differentiation (17,18), suggesting that Pkd1 may function in bone. Because homozygous PKD1/Pkd1 mutations in humans and mice are lethal, and most of the existing models are globally Pkd1-deficient, the significance of inactivation of Pkd1 in osteoblasts remains uncertain, and the bone changes might reflect an indirect effect due to loss of PKD1, in the kidney or other tissues.In the current study, to determine if PKD1 in osteoblasts has a direct function in regulating postnatal skeletal functions, we used mouse genetic approaches to conditionally delete Pkd1 in osteoblasts. We demonstrate that conditional deletion of Pkd1 from osteoblasts using Oc-Cre results defective osteoblast function in vivo and in vitro, and osteopenia, indicating that PKD1 has a direct role to regulate osteoblast function and skeletal homeostasis. EXPERIMENTAL PROCEDURES

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“…Skeletal malformations have been detected in unusual patients with this form of PKD (Turco et al, 1993). Mice with mutations in Pkd1 demonstrate defects in embryonic endochondral bone formation as well as osteopenia in adults (Boulter et al, 2001;Lu et al, 2001;Xiao et al, 2006).…”

Section: A Role For Ift/primary Cilia In Endochondral Bone Formatimentioning

confidence: 99%

Chapter 11 Cilia Involvement in Patterning and Maintenance of the Skeleton

Haycraft

Serra

2008

Current Topics in Developmental Biology

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Although the expression of cilia on chondrocytes was described over 40 years ago, the importance of this organelle in skeletal development and maintenance has only recently been recognized. Primary cilia are found on most mammalian cells and have been shown to play a role in chemosensation and mechanosensation. A growing number of human pleiotropic syndromes have been shown to be associated with ciliary or basal body dysfunction. Skeletal phenotypes, including alterations in limb patterning, endochondral bone formation, craniofacial development, and dentition, have been described in several of these syndromes. Additional insights into the potential roles and mechanisms of cilia action in the mammalian skeleton have been provided by research in model organisms including mouse and zebrafish. In this article we describe what is currently known about the localization of cilia in the skeleton as well as the roles and underlying molecular mechanisms of cilia in skeletal development.

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Molecular genetic diagnosis of autosomal dominant polycystic kidney disease in a newborn with bilateral cystic kidneys detected prenatally and multiple skeletal malformations.

Abstract: We report a case of an unusual prenatal presentation of polycystic kidneys associated with multiple skeletal limb defects, including polydactyly, syndactyly, bilat-

Cited by 26 publications

References 15 publications

Prenatal ultrasonographic findings of dominant polycystic kidney disease and postnatal renal evolution

Prenatal ultrasonographic findings of dominant polycystic kidney disease and postnatal renal evolution

Conditional Disruption of Pkd1 in Osteoblasts Results in Osteopenia Due to Direct Impairment of Bone Formation

Chapter 11 Cilia Involvement in Patterning and Maintenance of the Skeleton

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