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Article ; Online: Mutations in PVRL4, encoding cell adhesion molecule nectin-4, cause ectodermal dysplasia-syndactyly syndrome.

Brancati, Francesco / Fortugno, Paola / Bottillo, Irene / Lopez, Marc / Josselin, Emmanuelle / Boudghene-Stambouli, Omar / Agolini, Emanuele / Bernardini, Laura / Bellacchio, Emanuele / Iannicelli, Miriam / Rossi, Alfredo / Dib-Lachachi, Amina / Stuppia, Liborio / Palka, Giandomenico / Mundlos, Stefan / Stricker, Sigmar / Kornak, Uwe / Zambruno, Giovanna / Dallapiccola, Bruno

American journal of human genetics

2010 Volume 87, Issue 2, Page(s) 265–273

Abstract: Ectodermal dysplasias form a large disease family with more than 200 members. The combination of hair and tooth abnormalities, alopecia, and cutaneous syndactyly is characteristic of ectodermal dysplasia-syndactyly syndrome (EDSS). We used a homozygosity ...

Abstract	Ectodermal dysplasias form a large disease family with more than 200 members. The combination of hair and tooth abnormalities, alopecia, and cutaneous syndactyly is characteristic of ectodermal dysplasia-syndactyly syndrome (EDSS). We used a homozygosity mapping approach to map the EDSS locus to 1q23 in a consanguineous Algerian family. By candidate gene analysis, we identified a homozygous mutation in the PVRL4 gene that not only evoked an amino acid change but also led to exon skipping. In an Italian family with two siblings affected by EDSS, we further detected a missense and a frameshift mutation. PVRL4 encodes for nectin-4, a cell adhesion molecule mainly implicated in the formation of cadherin-based adherens junctions. We demonstrated high nectin-4 expression in hair follicle structures, as well as in the separating digits of murine embryos, the tissues mainly affected by the EDSS phenotype. In patient keratinocytes, mutated nectin-4 lost its capability to bind nectin-1. Additionally, in discrete structures of the hair follicle, we found alterations of the membrane localization of nectin-afadin and cadherin-catenin complexes, which are essential for adherens junction formation, and we found reorganization of actin cytoskeleton. Together with cleft lip and/or palate ectodermal dysplasia (CLPED1, or Zlotogora-Ogur syndrome) due to an impaired function of nectin-1, EDSS is the second known "nectinopathy" caused by mutations in a nectin adhesion molecule.
MeSH term(s)	Abnormalities, Multiple/genetics ; Adult ; Amino Acid Sequence ; Animals ; Cell Adhesion Molecules/chemistry ; Cell Adhesion Molecules/genetics ; Cell Adhesion Molecules/metabolism ; Child ; Ectodermal Dysplasia/complications ; Ectodermal Dysplasia/genetics ; Extremities/embryology ; Family ; Female ; Gene Expression Regulation, Developmental ; Hair/pathology ; Humans ; Male ; Mice ; Molecular Sequence Data ; Mutation/genetics ; Pedigree ; Protein Transport ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Skin/pathology ; Syndactyly/complications ; Syndactyly/genetics ; Syndrome
Chemical Substances	Cell Adhesion Molecules ; RNA, Messenger ; Nectin4 protein, mouse ; NECTIN4 protein, human
Language	English
Publishing date	2010-08-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2010.07.003
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Article ; Online: Delineation and diagnostic criteria of Oral-Facial-Digital Syndrome type VI.

Poretti, Andrea / Vitiello, Giuseppina / Hennekam, Raoul C M / Arrigoni, Filippo / Bertini, Enrico / Borgatti, Renato / Brancati, Francesco / D'Arrigo, Stefano / Faravelli, Francesca / Giordano, Lucio / Huisman, Thierry A G M / Iannicelli, Miriam / Kluger, Gerhard / Kyllerman, Marten / Landgren, Magnus / Lees, Melissa M / Pinelli, Lorenzo / Romaniello, Romina / Scheer, Ianina /

Schwarz, Christoph E / Spiegel, Ronen / Tibussek, Daniel / Valente, Enza Maria / Boltshauser, Eugen

Orphanet journal of rare diseases

2012 Volume 7, Page(s) 4

Abstract: Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post- ... ...

Abstract	Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the more severe neuroimaging findings. Based on the literature and this study we suggest as diagnostic criteria for OFD VI: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of one or more hands or feet; 3) hypothalamic hamartoma.
MeSH term(s)	Abnormalities, Multiple/diagnosis ; Abnormalities, Multiple/pathology ; Adolescent ; Adult ; Cerebellar Diseases/classification ; Cerebellar Diseases/diagnosis ; Cerebellar Diseases/genetics ; Cerebellar Diseases/pathology ; Cerebellum/abnormalities ; Child ; Child, Preschool ; Eye Abnormalities/classification ; Eye Abnormalities/diagnosis ; Eye Abnormalities/genetics ; Eye Abnormalities/pathology ; Female ; Humans ; Infant ; Infant, Newborn ; Kidney Diseases, Cystic/classification ; Kidney Diseases, Cystic/diagnosis ; Kidney Diseases, Cystic/genetics ; Kidney Diseases, Cystic/pathology ; Magnetic Resonance Imaging/methods ; Male ; Neuroimaging/methods ; Orofaciodigital Syndromes/classification ; Orofaciodigital Syndromes/diagnosis ; Orofaciodigital Syndromes/genetics ; Orofaciodigital Syndromes/pathology ; Phenotype ; Polydactyly/diagnosis ; Polydactyly/pathology ; Retina/abnormalities ; Retina/pathology ; Young Adult
Language	English
Publishing date	2012-01-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1750-1172
ISSN (online)	1750-1172
DOI	10.1186/1750-1172-7-4
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Article ; Online: Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders.

Travaglini, Lorena / Brancati, Francesco / Silhavy, Jennifer / Iannicelli, Miriam / Nickerson, Elizabeth / Elkhartoufi, Nadia / Scott, Eric / Spencer, Emily / Gabriel, Stacey / Thomas, Sophie / Ben-Zeev, Bruria / Bertini, Enrico / Boltshauser, Eugen / Chaouch, Malika / Cilio, Maria Roberta / de Jong, Mirjam M / Kayserili, Hulya / Ogur, Gonul / Poretti, Andrea /

Signorini, Sabrina / Uziel, Graziella / Zaki, Maha S / Johnson, Colin / Attié-Bitach, Tania / Gleeson, Joseph G / Valente, Enza Maria

European journal of human genetics : EJHG

2013 Volume 21, Issue 10, Page(s) 1074–1078

Abstract: Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for ... ...

Abstract	Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.
MeSH term(s)	Abnormalities, Multiple ; Adolescent ; Amino Acid Sequence ; Cerebellar Diseases/diagnosis ; Cerebellar Diseases/genetics ; Cerebellum/abnormalities ; Child ; Child, Preschool ; Ciliary Motility Disorders/diagnosis ; Ciliary Motility Disorders/genetics ; Encephalocele/diagnosis ; Encephalocele/genetics ; Eye Abnormalities/diagnosis ; Eye Abnormalities/genetics ; Female ; Gene Frequency ; Heterozygote ; Humans ; Infant ; Kidney Diseases, Cystic/diagnosis ; Kidney Diseases, Cystic/genetics ; Male ; Molecular Sequence Data ; Mutation ; Pedigree ; Phenotype ; Phosphoric Monoester Hydrolases/genetics ; Polycystic Kidney Diseases/diagnosis ; Polycystic Kidney Diseases/genetics ; Prenatal Diagnosis ; Prevalence ; Retina/abnormalities ; Retinitis Pigmentosa
Chemical Substances	Phosphoric Monoester Hydrolases (EC 3.1.3.2) ; phosphoinositide 5-phosphatase (EC 3.1.3.36)
Language	English
Publishing date	2013-02-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/ejhg.2012.305
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Article ; Online: Delineation and Diagnostic Criteria of Oral-Facial-Digital Syndrome Type VI

Poretti Andrea / Vitiello Giuseppina / Hennekam Raoul CM / Arrigoni Filippo / Bertini Enrico / Borgatti Renato / Brancati Francesco / D'Arrigo Stefano / Faravelli Francesca / Giordano Lucio / Huisman Thierry AGM / Iannicelli Miriam / Kluger Gerhard / Kyllerman Marten / Landgren Magnus / Lees Melissa M / Pinelli Lorenzo / Romaniello Romina / Scheer Ianina /

Schwarz Christoph E / Spiegel Ronen / Tibussek Daniel / Valente Enza / Boltshauser Eugen

Orphanet Journal of Rare Diseases, Vol 7, Iss 1, p

2012 Volume 4

Abstract: Abstract Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis ...

Abstract	Abstract Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the ...
Keywords	Joubert syndrome and related disorders ; Oral-facial-digital syndrome type VI ; neuroimaging ; molar tooth sign ; cerebellar malformation ; Medicine ; R
Subject code	616 ; 610
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium.

Lee, Ji Eun / Silhavy, Jennifer L / Zaki, Maha S / Schroth, Jana / Bielas, Stephanie L / Marsh, Sarah E / Olvera, Jesus / Brancati, Francesco / Iannicelli, Miriam / Ikegami, Koji / Schlossman, Andrew M / Merriman, Barry / Attié-Bitach, Tania / Logan, Clare V / Glass, Ian A / Cluckey, Andrew / Louie, Carrie M / Lee, Jeong Ho / Raynes, Hilary R /

Rapin, Isabelle / Castroviejo, Ignacio P / Setou, Mitsutoshi / Barbot, Clara / Boltshauser, Eugen / Nelson, Stanley F / Hildebrandt, Friedhelm / Johnson, Colin A / Doherty, Daniel A / Valente, Enza Maria / Gleeson, Joseph G

Nature genetics

2012 Volume 44, Issue 2, Page(s) 193–199

Abstract: Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and has been suggested to be important for ciliary function. However, its relationship to disorders of the primary cilium, termed ciliopathies, ... ...

Abstract	Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and has been suggested to be important for ciliary function. However, its relationship to disorders of the primary cilium, termed ciliopathies, has not been explored. Here we mapped a new locus for Joubert syndrome (JBTS), which we have designated as JBTS15, and identified causative mutations in CEP41, which encodes a 41-kDa centrosomal protein. We show that CEP41 is localized to the basal body and primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme. Depletion of CEP41 causes ciliopathy-related phenotypes in zebrafish and mice and results in glutamylation defects in the ciliary axoneme. Our data identify CEP41 mutations as a cause of JBTS and implicate tubulin post-translational modification in the pathogenesis of human ciliary dysfunction.
MeSH term(s)	Animals ; Centrosome/metabolism ; Cerebellar Diseases/genetics ; Chromosome Mapping ; Cilia/genetics ; Cilia/metabolism ; Ciliary Motility Disorders/genetics ; Eye Abnormalities/genetics ; Female ; Genetic Loci ; Glutamic Acid/metabolism ; Humans ; Male ; Mice ; Mutation ; Peptide Synthases/metabolism ; Polycystic Kidney Diseases/genetics ; Polymorphism, Single Nucleotide ; Protein Processing, Post-Translational ; Proteins/genetics ; Syndrome ; Tubulin/metabolism
Chemical Substances	CEP41 protein, human ; Proteins ; Tubulin ; Glutamic Acid (3KX376GY7L) ; Peptide Synthases (EC 6.3.2.-) ; TTLL6 protein, human (EC 6.3.2.-)
Language	English
Publishing date	2012-01-15
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.1078
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Zs.A 3613: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Evolutionarily assembled cis-regulatory module at a human ciliopathy locus.

Lee, Jeong Ho / Silhavy, Jennifer L / Lee, Ji Eun / Al-Gazali, Lihadh / Thomas, Sophie / Davis, Erica E / Bielas, Stephanie L / Hill, Kiley J / Iannicelli, Miriam / Brancati, Francesco / Gabriel, Stacey B / Russ, Carsten / Logan, Clare V / Sharif, Saghira Malik / Bennett, Christopher P / Abe, Masumi / Hildebrandt, Friedhelm / Diplas, Bill H / Attié-Bitach, Tania /

Katsanis, Nicholas / Rajab, Anna / Koul, Roshan / Sztriha, Laszlo / Waters, Elizabeth R / Ferro-Novick, Susan / Woods, C Geoffrey / Johnson, Colin A / Valente, Enza Maria / Zaki, Maha S / Gleeson, Joseph G

Science (New York, N.Y.)

2012 Volume 335, Issue 6071, Page(s) 966–969

Abstract: Neighboring genes are often coordinately expressed within cis-regulatory modules, but evidence that nonparalogous genes share functions in mammals is lacking. Here, we report that mutation of either TMEM138 or TMEM216 causes a phenotypically ... ...

Abstract	Neighboring genes are often coordinately expressed within cis-regulatory modules, but evidence that nonparalogous genes share functions in mammals is lacking. Here, we report that mutation of either TMEM138 or TMEM216 causes a phenotypically indistinguishable human ciliopathy, Joubert syndrome. Despite a lack of sequence homology, the genes are aligned in a head-to-tail configuration and joined by chromosomal rearrangement at the amphibian-to-reptile evolutionary transition. Expression of the two genes is mediated by a conserved regulatory element in the noncoding intergenic region. Coordinated expression is important for their interdependent cellular role in vesicular transport to primary cilia. Hence, during vertebrate evolution of genes involved in ciliogenesis, nonparalogous genes were arranged to a functional gene cluster with shared regulatory elements.
MeSH term(s)	Amino Acid Sequence ; Animals ; Cell Line ; Cerebellar Diseases/genetics ; Cerebellar Diseases/metabolism ; Cerebellar Diseases/pathology ; Cilia/metabolism ; Cilia/ultrastructure ; Conserved Sequence ; DNA, Intergenic ; Evolution, Molecular ; Eye Abnormalities/genetics ; Eye Abnormalities/metabolism ; Eye Abnormalities/pathology ; Gene Expression Profiling ; Gene Expression Regulation ; Genetic Heterogeneity ; Genetic Loci ; Humans ; Kidney Diseases, Cystic/genetics ; Kidney Diseases, Cystic/metabolism ; Kidney Diseases, Cystic/pathology ; Membrane Proteins/chemistry ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Molecular Sequence Data ; Multigene Family ; Mutation ; Mutation, Missense ; Phenotype ; Protein Transport ; Regulatory Sequences, Nucleic Acid ; Retina/abnormalities ; Retina/metabolism ; Retina/pathology ; Transport Vesicles/metabolism ; Transport Vesicles/ultrastructure
Chemical Substances	DNA, Intergenic ; Membrane Proteins ; TMEM138 protein, human ; TMEM216 protein, human
Language	English
Publishing date	2012-01-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.1213506
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Article ; Online: MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement.

Brancati, Francesco / Iannicelli, Miriam / Travaglini, Lorena / Mazzotta, Annalisa / Bertini, Enrico / Boltshauser, Eugen / D'Arrigo, Stefano / Emma, Francesco / Fazzi, Elisa / Gallizzi, Romina / Gentile, Mattia / Loncarevic, Damir / Mejaski-Bosnjak, Vlatka / Pantaleoni, Chiara / Rigoli, Luciana / Salpietro, Carmelo D / Signorini, Sabrina / Stringini, Gilda Rita / Verloes, Alain /

Zabloka, Dominika / Dallapiccola, Bruno / Gleeson, Joseph G / Valente, Enza Maria

Human mutation

2008 Volume 30, Issue 2, Page(s) E432–42

Abstract: The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the "molar tooth sign", a midbrain-hindbrain malformation pathognomonic for ... ...

Abstract	The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the "molar tooth sign", a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs.
MeSH term(s)	Abnormalities, Multiple/genetics ; Amino Acid Sequence ; Base Sequence ; DNA Mutational Analysis ; Humans ; Liver/pathology ; Magnetic Resonance Imaging ; Membrane Proteins/chemistry ; Membrane Proteins/genetics ; Molecular Sequence Data ; Mutation/genetics ; Phenotype ; RNA Splice Sites/genetics ; Syndrome
Chemical Substances	Membrane Proteins ; RNA Splice Sites ; TMEM67 protein, human
Language	English
Publishing date	2008-12-04
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.20924
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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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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 /

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 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

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Article: Evolutionarily Assembled cis-Regulatory Module at a Human Ciliopathy Locus

Lee, Jeong Ho / Anna Rajab / Bill H. Diplas / C. Geoffrey Woods / Carsten Russ / Christopher P. Bennett / Clare V. Logan / Colin A. Johnson / Elizabeth R. Waters / Enza Maria Valente / Erica E. Davis / Francesco Brancati / Friedhelm Hildebrandt / Jennifer L. Silhavy / Ji Eun Lee / Joseph G. Gleeson / Kiley J. Hill / Laszlo Sztriha / Lihadh Al-Gazali /

Maha S. Zaki / Masumi Abe / Miriam Iannicelli / Nicholas Katsanis / Roshan Koul / Saghira Malik Sharif / Sophie Thomas / Stacey B. Gabriel / Stephanie L. Bielas / Susan Ferro-Novick / Tania AttiÃ©-Bitach

Science. 2012 Feb. 24, v. 335, no. 6071

2012

Abstract	Neighboring genes are often coordinately expressed within cis-regulatory modules, but evidence that nonparalogous genes share functions in mammals is lacking. Here, we report that mutation of either TMEM138 or TMEM216 causes a phenotypically indistinguishable human ciliopathy, Joubert syndrome. Despite a lack of sequence homology, the genes are aligned in a head-to-tail configuration and joined by chromosomal rearrangement at the amphibian-to-reptile evolutionary transition. Expression of the two genes is mediated by a conserved regulatory element in the noncoding intergenic region. Coordinated expression is important for their interdependent cellular role in vesicular transport to primary cilia. Hence, during vertebrate evolution of genes involved in ciliogenesis, nonparalogous genes were arranged to a functional gene cluster with shared regulatory elements.
Keywords	chromosome aberrations ; cilia ; evolution ; humans ; intergenic DNA ; loci ; multigene family ; mutation ; regulatory sequences ; sequence homology
Language	English
Dates of publication	2012-0224
Size	p. 966-969.
Publishing place	American Association for the Advancement of Science
Document type	Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.1213506
Database	NAL-Catalogue (AGRICOLA)

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