Article

Identification of CC2D2A as a Meckel Syndrome Gene Adds an Important Piece to the Ciliopathy Puzzle

National Public Health Institute, Institute for Molecular Medicine Finland, Helsinki 00290, Finland.
The American Journal of Human Genetics (Impact Factor: 10.99). 07/2008; 82(6):1361-7. DOI: 10.1016/j.ajhg.2008.05.004
Source: PubMed

ABSTRACT Meckel syndrome (MKS) is a lethal malformation disorder characterized classically by encephalocele, polycystic kidneys, and polydactyly. MKS is also one of the major contributors to syndromic neural tube defects (NTDs). Recent findings have shown primary cilia dysfunction in the molecular background of MKS, indicating that cilia are critical for early human development. However, even though four genes behind MKS have been identified to date, they elucidate only a minor proportion of the MKS cases. In this study, instead of traditional linkage analysis, we selected 10 nonrelated affected fetuses and looked for the homozygous regions shared by them. Based on this strategy, we identified the sixth locus and the fifth gene, CC2D2A (MKS6), behind MKS. The biological function of CC2D2A is uncharacterized, but the corresponding polypeptide is predicted to be involved in ciliary functions and it has a calcium binding domain (C2). Immunofluorescence staining of patient's fibroblast cells demonstrates that the cells lack cilia, providing evidence for the critical role of CC2D2A in cilia formation. Our finding is very significant not only to understand the molecular background of MKS, but also to obtain additional information about the function of the cilia, which can help to understand their significance in normal development and also in other ciliopathies, which are an increasing group of disorders with overlapping phenotypes.

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    • "To date, mutations in 16 genes have been linked to this group of disorders: NPHP1–9, AHI1/Jouberin, ARL13B, INPP5E, TMEM216, MKS1, MKS3/TMEM67, and MKS6/CC2D2A (Tallila et al., 2008; Hildebrandt et al., 2009a; Lee and Gleeson 2010; Supplemental References). Interestingly, different alleles of the same gene can result in the phenotypic spectrum of NPHP, JBTS, and MKS. "
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    ABSTRACT: Nephronophthisis (NPHP), Joubert (JBTS), and Meckel-Gruber (MKS) syndromes are autosomal-recessive ciliopathies presenting with cystic kidneys, retinal degeneration, and cerebellar/neural tube malformation. Whether defects in kidney, retinal, or neural disease primarily involve ciliary, Hedgehog, or cell polarity pathways remains unclear. Using high-confidence proteomics, we identified 850 interactors copurifying with nine NPHP/JBTS/MKS proteins and discovered three connected modules: "NPHP1-4-8" functioning at the apical surface, "NPHP5-6" at centrosomes, and "MKS" linked to Hedgehog signaling. Assays for ciliogenesis and epithelial morphogenesis in 3D renal cultures link renal cystic disease to apical organization defects, whereas ciliary and Hedgehog pathway defects lead to retinal or neural deficits. Using 38 interactors as candidates, linkage and sequencing analysis of 250 patients identified ATXN10 and TCTN2 as new NPHP-JBTS genes, and our Tctn2 mouse knockout shows neural tube and Hedgehog signaling defects. Our study further illustrates the power of linking proteomic networks and human genetics to uncover critical disease pathways.
    Cell 05/2011; 145(4):513-28. DOI:10.1016/j.cell.2011.04.019 · 33.12 Impact Factor
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    • "Figure S1). All mutations found in the MKS in this study (14) and the previously reported Finnish mutation (Tallila et al., 2008) predicted null alleles (15/15 mutations). By contrast, all but two patients with JBS and CC2D2A mutations reported here and in previous studies (Gorden et al., 2008; Noor et al., 2008) have at least one missense mutation (10/12). "
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    ABSTRACT: Meckel-Gruber syndrome (MKS) is a lethal fetal disorder characterized by diffuse renal cystic dysplasia, polydactyly, a brain malformation that is usually occipital encephalocele, and/or vermian agenesis, with intrahepatic biliary duct proliferation. Joubert syndrome (JBS) is a viable neurological disorder with a characteristic "molar tooth sign" (MTS) on axial images reflecting cerebellar vermian hypoplasia/dysplasia. Both conditions are classified as ciliopathies with an autosomal recessive mode of inheritance. Allelism of MKS and JBS has been reported for TMEM67/MKS3, CEP290/MKS4, and RPGRIP1L/MKS5. Recently, one homozygous splice mutation with a founder effect was reported in the CC2D2A gene in Finnish fetuses with MKS, defining the 6th locus for MKS. Shortly thereafter, CC2D2A mutations were also reported in JBS. The analysis of the CC2D2A gene in our series of MKS fetuses, identified 14 novel truncating mutations in 11 cases. These results confirm the involvement of CC2D2A in MKS and reveal a major contribution of CC2D2A to the disease. We also identified three missense CC2D2A mutations in two JBS cases. Therefore, and in accordance with the data reported regarding RPGRIP1L, our results indicate phenotype-genotype correlations, as missense and presumably hypomorphic mutations lead to JBS while all null alleles lead to MKS.
    Human Mutation 09/2009; 30(11):1574-82. DOI:10.1002/humu.21116 · 5.05 Impact Factor
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    ABSTRACT: Hydrolethalus syndrome (HLS) is a severe fetal malformation syndrome that is inherited by an autosomal recessive manner. HLS belongs to the Finnish disease heritage, an entity of rare diseases that are more prevalent in Finland than in other parts of the world. The phenotypic spectrum of the syndrome is wide and it is characterized by several developmental abnormalities, including hydrocephalus and absent midline structures in the brain, abnormal lobation of the lungs, polydactyly as well as micrognathia and other craniofacial anomalies. Polyhydramnios are relatively frequent during pregnancy. HLS can nowadays be effectively identified by ultrasound scan already at the end of the first trimester of pregnancy. One of the main goals in this study was to identify and characterize the gene defect underlying HLS. The defect was found from a previously unknown gene that was named HYLS1. Identification of the gene defect made it possible to confirm the HLS diagnosis genetically, an aspect that provides valuable information for the families in which a fetus is suspected to have HLS. Neuropathological findings of mutation confirmed HLS cases were described for the first time in detail in this study. Also, detailed general pathological findings were described. Since HYLS1 was an unknown gene with no relatives in the known gene families, many functional studies were performed in order to unravel the function of the gene and of the protein it codes for. Studies showed, for example, that the subcellular localization of the HYLS1 protein was different when the normal and the defective forms were compared. In addition, HYLS1 was shown to possess transactivation potential which was significantly diminished in the defective form. According to the results of this study it can be stated that HYLS1 most likely participates in transcriptional regulation and also in the regulation of cholesterol metabolism and that the function of HYLS1 is critical for normal fetal development. Hydroletalus-oireyhtymä (HLS) on suomalaiseen tautiperintöön kuuluva, autosomaalisesti peittyvästi periytyvä vakava oireyhtymä, joka ilmenee jo sikiönkehityksen aikana. Oireyhtymän ilmiasun kirjo on laaja ja tyypillisiä piirteitä on useita, näistä yleisimpinä keskushermoston epänormaalit rakenteet kuten vesipäisyys ja aivojen keskiviivan rakenteiden puutos, keuhkojen epänormaali lohkojako, polydaktylia eli ylimääräiset sormet ja varpaat sekä pienileukaisuus ja muut kasvojen rakenteiden poikkeavuudet. Lapsiveden määrä loppuraskaudessa on usein moninkertainen normaaliin raskauteen verrattuna. Nykyään HLS pystytään tunnistamaan luotettavasti ultraäänitutkimuksen avulla jopa jo ensimmäisen raskauskolmanneksen lopulla. Tutkimuksen yhtenä päätavoitteena oli tunnistaa ja karakterisoida geeni, jossa oleva virhe johtaa HLS:n syntyyn. Geenivirhe löydettiin aiemmin tuntemattomasta geenistä, jolle annettiin nimi HYLS1 oireyhtymän mukaan. Geenivirheen tunnistaminen toi tärkeän mahdollisuuden HLS-diagnoosin geneettiseen varmentamiseen. Tämän myötä voidaan tarjota hyödyllistä geneettistä tietoa perheille, joissa epäillään sikiöllä olevan hydroletalus-oireyhtymä. Tämän tutkimuksen aikana kuvattiin myös ensimmäistä kertaa yksityiskohtaiset neuropatologiset löydökset HLS-tapauksista, joiden HYLS1-geenivirhe oli varmennettu. Neuropatologisten löydösten lisäksi kuvattiin myös yleiset patologiset löydökset yksityiskohtaisesti. Koska HYLS1 oli aiemmin tuntematon geeni eikä se kuulunut mihinkään aiemmin tunnettuun geeniperheeseen, väitöstyössä tehtiin monia toiminnallisia tutkimuksia geenin ja sen koodaaman proteiinin toiminnan selvittämiseksi. Tutkimuksissa saatiin muun muassa selville, että HYLS1-proteiinin normaalimuodon ja virheellisen muodon solunsisäinen sijainti on erilainen. Lisäksi HYLS1:lla havaittiin olevan geeniluennan eli transkription aloitukseen liittyvää aktiivisuutta, joka oli merkittävästi pienentynyt silloin, kun proteiini on geenivirheen seurauksena viallinen. Väitöstutkimuksen tulosten perusteella voidaan todeta, että HYLS1 on mitä todennäköisimmin solun transkription säätelyyn ja ehkä myös kolesterolimetabolian säätelyyn osallistuva proteiini, jolla on hyvin keskeinen tehtävä sikiönkehityksen aikana.
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