Renal-hepatic-pancreatic dysplasia: An autosomal recessive disorder with renal and hepatic failure

Neuhaus, Thomas J.; Sennhauser, Felix H.; Briner, J; Damme, Boudewijn Van; Leumann, Ernst

doi:10.1007/bf02002909

Cited by 12 publications

(12 citation statements)

References 20 publications

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“…Clinical data of a nonconsanguineous Swiss multiplex family (F917) with renal-hepatic-pancreatic dysplasia has been previously described in detail (Table 1). 20 Paternally, in exon 20, the novel missense mutation c.2918G / A (p.Arg973Gln) that affects an evolutionarily highly conserved arginine residue and was not present among 400 control chromosomes was identified. Maternally, the novel nonsense mutation c.3340C / T (p.Gln1114X) was detected in exon 24 (Figure 2).…”

Section: Resultsmentioning

confidence: 99%

Loss of Nephrocystin-3 Function Can Cause Embryonic Lethality, Meckel-Gruber-like Syndrome, Situs Inversus, and Renal-Hepatic-Pancreatic Dysplasia

Bergmann

Fliegauf

Brüchle

et al. 2008

The American Journal of Human Genetics

300

275

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Many genetic diseases have been linked to the dysfunction of primary cilia, which occur nearly ubiquitously in the body and act as solitary cellular mechanosensory organelles. The list of clinical manifestations and affected tissues in cilia-related disorders (ciliopathies) such as nephronophthisis is broad and has been attributed to the wide expression pattern of ciliary proteins. However, little is known about the molecular mechanisms leading to this dramatic diversity of phenotypes. We recently reported hypomorphic NPHP3 mutations in children and young adults with isolated nephronophthisis and associated hepatic fibrosis or tapetoretinal degeneration. Here, we chose a combinatorial approach in mice and humans to define the phenotypic spectrum of NPHP3/Nphp3 mutations and the role of the nephrocystin-3 protein. We demonstrate that the pcy mutation generates a hypomorphic Nphp3 allele that is responsible for the cystic kidney disease phenotype, whereas complete loss of Nphp3 function results in situs inversus, congenital heart defects, and embryonic lethality in mice. In humans, we show that NPHP3 mutations can cause a broad clinical spectrum of early embryonic patterning defects comprising situs inversus, polydactyly, central nervous system malformations, structural heart defects, preauricular fistulas, and a wide range of congenital anomalies of the kidney and urinary tract (CAKUT). On the functional level, we show that nephrocystin-3 directly interacts with inversin and can inhibit like inversin canonical Wnt signaling, whereas nephrocystin-3 deficiency leads in Xenopus laevis to typical planar cell polarity defects, suggesting a role in the control of canonical and noncanonical (planar cell polarity) Wnt signaling.

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Section: Resultsmentioning

confidence: 99%

Loss of Nephrocystin-3 Function Can Cause Embryonic Lethality, Meckel-Gruber-like Syndrome, Situs Inversus, and Renal-Hepatic-Pancreatic Dysplasia

Bergmann

Fliegauf

Brüchle

et al. 2008

The American Journal of Human Genetics

300

275

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“…Most RHPD patients die neonatally and some presented with Potter sequence. Only one case reported by Neuhaus et al [1996] was still alive at the age of 6 years after combined liver–kidney transplantation. This patient had no pancreatic involvement.…”

Section: Discussionmentioning

confidence: 99%

Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: A new autosomal recessive syndrome?

Taha

Barbar

Kanaan

et al. 2003

American J of Med Genetics Pt A

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We report on two sibs (of 4) with a syndrome of minor facial anomalies, proportionate IUGR, neonatal non-autoimmune diabetes mellitus (NDM), severe congenital hypothyroidism (CH), cholestasis, congenital glaucoma, and polycystic kidneys. Liver disease progressed to hepatic fibrosis. The renal disease was characterized by large kidneys and multiple small cysts with deficient corticomedullary junction differentiation and normal kidney function. The phenotype observed in the two sibs was identical. Although a combination of liver, kidney, and pancreatic involvement has been described in Ivemark syndrome (hepato-renal-pancreatic syndrome), the coexistence of NDM, CH, and glaucoma in both sibs suggests the possibility that this combination of manifestations describes a new autosomal recessive syndrome. Mutation analysis for several candidate genes is warranted.

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“…Other complex syndromes [Adès et al, 1994] can combine several findings of Cumming syndrome. Thus, Ivemark et al [1959] and others [Bernstein et al, 1987, Neuhaus et al, 1996, Torra et al, 1996 described a combination of renal, pancreatic, and liver dysplasia with autosomal recessive inheritance. Involvement of other organs, and the lack of campomelia and external malformations of Cumming syndrome, can exclude the renal-hepatic-pancreatic dysplasia syndrome.…”

Section: Discussionmentioning

confidence: 99%

“…Involvement of other organs, and the lack of campomelia and external malformations of Cumming syndrome, can exclude the renal-hepatic-pancreatic dysplasia syndrome. Some authors [Torra et al, 1996] propose that dysplasia could be a nonspecific final common pathway of response of affected organs to a variety of disturbances, including those caused by mutations in different genes; it could even constitute a widespread spectrum of disease [Neuhaus et al, 1996], with changeable manifestations.…”

Section: Discussionmentioning

confidence: 99%

Two new cases of Cumming syndrome confirming autosomal recessive inheritance

et al. 1999

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Renal-hepatic-pancreatic dysplasia: An autosomal recessive disorder with renal and hepatic failure

Abstract: Renal-hepatic-pancreatic dysplasia is an autosomal recessive disorder with variable expression. Combined liver-kidney transplantation offers a new therapeutic option.

Cited by 12 publications

References 20 publications

Loss of Nephrocystin-3 Function Can Cause Embryonic Lethality, Meckel-Gruber-like Syndrome, Situs Inversus, and Renal-Hepatic-Pancreatic Dysplasia

Loss of Nephrocystin-3 Function Can Cause Embryonic Lethality, Meckel-Gruber-like Syndrome, Situs Inversus, and Renal-Hepatic-Pancreatic Dysplasia

Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: A new autosomal recessive syndrome?

Two new cases of Cumming syndrome confirming autosomal recessive inheritance

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