Hypomorphic mutations in Meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11)

Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109-5646, USA.
Journal of Medical Genetics (Impact Factor: 6.34). 07/2009; 46(10):663-70. DOI: 10.1136/jmg.2009.066613
Source: PubMed


Nephronophthisis (NPHP), a rare recessive cystic kidney disease, is the most frequent genetic cause of chronic renal failure in children and young adults. Mutations in nine genes (NPHP1-9) have been identified. NPHP can be associated with retinal degeneration (Senior-Løken syndrome), brainstem and cerebellar anomalies (Joubert syndrome), or liver fibrosis.
To identify a causative gene for the subset of patients with associated liver fibrosis, the authors performed a genome wide linkage search in a consanguineous family with three affected patients using 50K SNP microarrays and homozygosity mapping.
The authors obtained a significant maximum parametric LOD (logarithm of odds) score of Z(max) = 3.72 on chromosome 8q22 and identified a homozygous missense mutation in the gene MKS3/TMEM67. When examining a worldwide cohort of 62 independent patients with NPHP and associated liver fibrosis we identified altogether four novel mutations (p.W290L, p.C615R, p.G821S, and p.G821R) in five of them. Mutations of MKS3/TMEM67, found recently in Meckel-Gruber syndrome (MKS) type 3 and Joubert syndrome (JBTS) type 6, are predominantly truncating mutations. In contrast, the mutations detected here in patients with NPHP and associated liver fibrosis are exclusively missense mutations. This suggests that they may represent hypomorphic alleles, leading to a milder phenotype compared with the more severe MKS or JBTS phenotype. Additionally, mutation analysis for MKS3/TMEM67 in 120 patients with JBTS yielded seven different (four novel) mutations in five patients, four of whom also presented with congenital liver fibrosis.
Hypomorphic MKS3/TMEM67 mutations cause NPHP with liver fibrosis (NPHP11). This is the first report of MKS3 mutations in patients with no vermian agenesis and without neurological signs. Thus NPHP, JBTS, and MKS represent allelic disorders.

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    • "Adding molecular diagnosis to classical clinical findings can be valuable in clarifying possible pathogenic mechanism(s). For example, the distinction between nephronophthisis (NPHP) and Senior–Løken syndrome (SLSN) depends on the presence of retinal findings in SLSN; however, individuals in NPHP pedigrees can also manifest ocular defects [28]. Similarly, the distinction between COACH syndrome (Joubert syndrome with congenital hepatic fibrosis) and JBTS is blurry. "
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    ABSTRACT: Ciliopathies encompass a broad array of clinical findings associated with genetic defects in biogenesis and/or function of the primary cilium, a ubiquitous organelle involved in the transduction of diverse biological signals. Degeneration or dysfunction of retinal photoreceptors is frequently observed in diverse ciliopathies. The sensory cilium in a photoreceptor elaborates into unique outer segment discs that provide extensive surface area for maximal photon capture and efficient visual transduction. The daily renewal of approximately 10% of outer segments requires a precise control of ciliary transport. Here, we review the ciliopathies with associated retinal degeneration, describe the distinctive structure of the photoreceptor cilium, and discuss mouse models that allow investigations into molecular mechanisms of cilia biogenesis and defects. We have specifically focused on two ciliary proteins -- CEP290 and RPGR -- that underlie photoreceptor degeneration and syndromic ciliopathies. Mouse models of CEP290 and RPGR disease, and of their multiple interacting partners, have helped unravel new functional insights into cell type-specific phenotypic defects in distinct ciliary proteins. Elucidation of multifaceted ciliary functions and associated protein complexes will require concerted efforts to assimilate diverse datasets from in vivo and in vitro studies. We therefore discuss a possible framework for investigating genetic networks associated with photoreceptor cilia biogenesis and pathology.
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    • "It is characterized by chronic tubulointerstitial nephritis that progresses to ESRD during the second decade. To date, the mutations in 9 genes (NPHP1-9) have been identified as the causative agents which are responsible for nephronophthisis [10] . Basically, there are three clinical variants of nephronophthisis according to the age of onset of the ESRD [4]. "
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    ABSTRACT: We are describing two sisters with the rare Senior-Loken syndrome, which is a combination of familial juvenile nephronophthisis and retinal dystrophy. The earliest presenting features include an impaired urinary concentrating ability, leading to polyuria and polydipsia and these are associated with visual impairment. The two patients had blindness shortly after their births. They presented to us with evidence of chronic kidney disease (CKD) in their teens, that required the initiation of the renal replacement therapy. We are reporting these two cases, as this was the first occurrence of this condition in the State of Qatar.
    Full-text · Article · Oct 2012 · Journal of Clinical and Diagnostic Research
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    • "In IV-1 there is mild cerebellar vermis hypoplasia without the MTS. et al., 2007; Otto et al., 2009; Valente et al., 2010]. In each case, the gene is primarily associated with one of the two disorders but some percentage of patients with mutations display features of both diseases. "
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    ABSTRACT: Disorders within the "ciliopathy" spectrum include Joubert (JS), Bardet-Biedl syndromes (BBS), and nephronophthisis (NPHP). Although mutations in single ciliopathy genes can lead to these different syndromes between families, there have been no reports of phenotypic discordance within a single family. We report on two consanguineous families with discordant ciliopathies in sibling. In Ciliopathy-672, the older child displayed dialysis-dependent NPHP whereas the younger displayed the pathognomonic molar tooth MRI sign (MTS) of JS. A second branch displayed two additional children with NPHP. In Ciliopathy-1491, the oldest child displayed classical features of BBS whereas the two younger children displayed the MTS. Importantly, the children with BBS and NPHP lacked MTS, whereas children with JS lacked obesity or NPHP, and the child with BBS lacked MTS and NPHP. Features common to all three disorders included intellectual disability, postaxial polydactyly, and visual reduction. The variable phenotypic expressivity in this family suggests that genetic modifiers may determine specific clinical features within the ciliopathy spectrum.
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