Dataset Information

MKS3-related ciliopathy with features of autosomal recessive polycystic kidney disease, nephronophthisis, and Joubert Syndrome.

ABSTRACT:

Objectives

To describe 3 children with mutations in a Meckel syndrome gene (MKS3), with features of autosomal recessive polycystic kidney disease (ARPKD), nephronophthisis, and Joubert syndrome (JS).

Study design

Biochemical evaluations, magnetic resonance and ultrasound imaging, electroretinograms, IQ testing, and sequence analysis of the PKHD1 and MKS3 genes were performed. Functional consequences of the MKS3 mutations were evaluated by cDNA sequencing and transfection studies with constructs of meckelin, the protein product of MKS3.

Results

These 3 children with MKS3 mutations had features typical of ARPKD, that is, enlarged, diffusely microcystic kidneys and early-onset severe hypertension. They also exhibited early-onset chronic anemia, a feature of nephronophthisis, and speech and oculomotor apraxia, suggestive of JS. Magnetic resonance imaging of the brain, originally interpreted as normal, revealed midbrain and cerebellar abnormalities in the spectrum of the "molar tooth sign" that characterizes JS.

Conclusions

These findings expand the phenotypes associated with MKS3 mutations. MKS3-related ciliopathies should be considered in patients with an ARPKD-like phenotype, especially in the presence of speech and oculomotor apraxia. In such patients, careful expert evaluation of the brain images can be beneficial because the brain malformations can be subtle.

SUBMITTER: Gunay-Aygun M

PROVIDER: S-EPMC2925444 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Publications

MKS3-related ciliopathy with features of autosomal recessive polycystic kidney disease, nephronophthisis, and Joubert Syndrome.

Gunay-Aygun Meral M Parisi Melissa A MA Doherty Dan D Tuchman Maya M Tsilou Ekaterini E Kleiner David E DE Huizing Marjan M Turkbey Baris B Choyke Peter P Guay-Woodford Lisa L Heller Theo T Szymanska Katarzyna K Johnson Colin A CA Glass Ian I Gahl William A WA

The Journal of pediatrics 20090621 3

<h4>Objectives</h4>To describe 3 children with mutations in a Meckel syndrome gene (MKS3), with features of autosomal recessive polycystic kidney disease (ARPKD), nephronophthisis, and Joubert syndrome (JS).<h4>Study design</h4>Biochemical evaluations, magnetic resonance and ultrasound imaging, electroretinograms, IQ testing, and sequence analysis of the PKHD1 and MKS3 genes were performed. Functional consequences of the MKS3 mutations were evaluated by cDNA sequencing and transfection studies w ...[more]

PMID: 19540516

Similar Datasets

Project description:Background and objectivesAutosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene. The longest open reading frame comprises 66 exons encoding polyductin or fibrocystin, a type I transmembrane protein with 4074 amino acids. Functional investigations are considerably hampered by its large size and lack of expression in tissues that are usually available for analysis such as lymphocytes or fibroblasts.Design, setting, participants, & measurementsAllegedly strong and clear-cut genotype-phenotype correlations for the type of PKHD1 mutation could be established. Thus far, practically all patients with two truncating mutations showed perinatal or neonatal demise and at least one hypomorphic missense mutation is thought to be indispensable for survival. Mutation analysis of >500 ARPKD families was performed by conventional and next-generation sequencing techniques.ResultsThis study presents four unrelated patients with ARPKD with a nonlethal, moderate clinical course despite the burden of two PKHD1 mutations expected to lead to premature termination of translation. In line with parental consanguinity, all mutations occurred in the homozygous state and segregated with the disorder in these families. To try to unravel the mechanisms that underlie this obvious contradiction, these patients were further analyzed in detail by utilizing different methods. In all cases, complex transcriptional alterations were detected. Alternative splicing patterns might disrupt a critical stoichiometric and temporal balance between different protein products and may play a crucial role in defining the phenotype of these patients.ConclusionsAlthough these findings represent rare events, they are of importance for genetic counseling and illustrate that some caution is warranted in the interpretation of mutations and their clinical significance. The authors hypothesize that expression of a minimal amount of functional protein is needed for survival of the neonatal period in ARPKD.

Dataset Information

MKS3-related ciliopathy with features of autosomal recessive polycystic kidney disease, nephronophthisis, and Joubert Syndrome.

Objectives

Study design

Results

Conclusions

Publications

MKS3-related ciliopathy with features of autosomal recessive polycystic kidney disease, nephronophthisis, and Joubert Syndrome.

Similar Datasets

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