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  1. Article: Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies

    Iannicelli, Miriam / Brancati, Francesco / Mougou-Zerelli, Soumaya / Mazzotta, Annalisa / Thomas, Sophie / Elkhartoufi, Nadia / Travaglini, Lorena / Gomes, Céline / Luigi Ardissino, Gian / Bertini, Enrico / Boltshauser, Eugen / Castorina, Pierangela / D'Arrigo, Stefano / Fischetto, Rita / Leroy, Brigitte / Loget, Philippe / Bonnière, Maryse / Starck, Lena / Tantau, Julia /
    Gentilin, Barbara / Majore, Silvia / Swistun, Dominika / Flori, Elizabeth / Lalatta, Faustina / Pantaleoni, Chiara / Penzien, Johannes / Grammatico, Paola / Dallapiccola, Bruno / Gleeson, Joseph G / Attie-Bitach, Tania / Valente, Enza Maria

    Human mutation. 2010 May, v. 31, no. 5

    2010  

    Abstract: Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic ... ...

    Abstract Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.
    Language English
    Dates of publication 2010-05
    Size p. E1319-E1331.
    Publishing place Wiley Subscription Services, Inc., A Wiley Company
    Document type Article
    ZDB-ID 1126646-6
    ISSN 1098-1004 ; 1059-7794
    ISSN (online) 1098-1004
    ISSN 1059-7794
    DOI 10.1002/humu.21239
    Database NAL-Catalogue (AGRICOLA)

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    Zs.A 3586: Show issues Location:
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  2. Article ; Online: Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies.

    Iannicelli, Miriam / Brancati, Francesco / Mougou-Zerelli, Soumaya / Mazzotta, Annalisa / Thomas, Sophie / Elkhartoufi, Nadia / Travaglini, Lorena / Gomes, Céline / Ardissino, Gian Luigi / Bertini, Enrico / Boltshauser, Eugen / Castorina, Pierangela / D'Arrigo, Stefano / Fischetto, Rita / Leroy, Brigitte / Loget, Philippe / Bonnière, Maryse / Starck, Lena / Tantau, Julia /
    Gentilin, Barbara / Majore, Silvia / Swistun, Dominika / Flori, Elizabeth / Lalatta, Faustina / Pantaleoni, Chiara / Penzien, Johannes / Grammatico, Paola / Dallapiccola, Bruno / Gleeson, Joseph G / Attie-Bitach, Tania / Valente, Enza Maria

    Human mutation

    2010  Volume 31, Issue 5, Page(s) E1319–31

    Abstract: Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic ... ...

    Abstract Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.
    MeSH term(s) Abnormalities, Multiple/genetics ; DNA Mutational Analysis ; Female ; Genotype ; Humans ; Kidney Diseases, Cystic/genetics ; Kidney Diseases, Cystic/pathology ; Liver Cirrhosis/genetics ; Liver Cirrhosis/pathology ; Membrane Proteins/genetics ; Mutation/genetics ; Phenotype ; Pregnancy ; Prenatal Diagnosis
    Chemical Substances Membrane Proteins ; TMEM67 protein, human
    Language English
    Publishing date 2010-03-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1126646-6
    ISSN 1098-1004 ; 1059-7794
    ISSN (online) 1098-1004
    ISSN 1059-7794
    DOI 10.1002/humu.21239
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

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    In stock of ZB MED Cologne/Königswinter

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  3. Article ; Online: KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes.

    Putoux, Audrey / Thomas, Sophie / Coene, Karlien L M / Davis, Erica E / Alanay, Yasemin / Ogur, Gönül / Uz, Elif / Buzas, Daniela / Gomes, Céline / Patrier, Sophie / Bennett, Christopher L / Elkhartoufi, Nadia / Frison, Marie-Hélène Saint / Rigonnot, Luc / Joyé, Nicole / Pruvost, Solenn / Utine, Gulen Eda / Boduroglu, Koray / Nitschke, Patrick /
    Fertitta, Laura / Thauvin-Robinet, Christel / Munnich, Arnold / Cormier-Daire, Valérie / Hennekam, Raoul / Colin, Estelle / Akarsu, Nurten Ayse / Bole-Feysot, Christine / Cagnard, Nicolas / Schmitt, Alain / Goudin, Nicolas / Lyonnet, Stanislas / Encha-Razavi, Férechté / Siffroi, Jean-Pierre / Winey, Mark / Katsanis, Nicholas / Gonzales, Marie / Vekemans, Michel / Beales, Philip L / Attié-Bitach, Tania

    Nature genetics

    2011  Volume 43, Issue 6, Page(s) 601–606

    Abstract: KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping ... ...

    Abstract KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies.
    MeSH term(s) Acrocallosal Syndrome/genetics ; Acrocallosal Syndrome/pathology ; Adolescent ; Cerebral Ventricles/pathology ; Child ; Child, Preschool ; Cilia/genetics ; Consanguinity ; Female ; Hand Deformities, Congenital/embryology ; Hand Deformities, Congenital/genetics ; Hand Deformities, Congenital/pathology ; Heart Defects, Congenital/embryology ; Heart Defects, Congenital/genetics ; Heart Defects, Congenital/pathology ; Hedgehog Proteins/metabolism ; Humans ; Hydrocephalus/embryology ; Hydrocephalus/genetics ; Hydrocephalus/pathology ; Infant ; Kinesins/genetics ; Magnetic Resonance Imaging ; Male ; Mutation ; Pedigree
    Chemical Substances Hedgehog Proteins ; KIF7 protein, human ; Kinesins (EC 3.6.4.4)
    Language English
    Publishing date 2011-05-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/ng.826
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3613: Show issues Location:
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    Zs.MG 46: Show issues

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