Novel TMEM67 Mutations and Genotype-phenotype Correlates in Meckelin-related Ciliopathies

被引：82

作者：

Iannicelli, Miriam ^{[2
]}

Brancati, Francesco ^{[2
,3
,4
]}

Mougou-Zerelli, Soumaya ^{[5
,6
]}

Mazzotta, Annalisa ^{[2
]}

Thomas, Sophie ^{[5
,6
]}

Elkhartoufi, Nadia ^{[7
]}

Travaglini, Lorena ^{[2
]}

Gomes, Celine ^{[5
,6
]}

Ardissino, Gian Luigi ^{[8
]}

Bertini, Enrico ^{[9
]}

Boltshauser, Eugen ^{[10
]}

Castorina, Pierangela ^{[8
]}

D'Arrigo, Stefano ^{[11
]}

Fischetto, Rita ^{[12
]}

Leroy, Brigitte ^{[13
]}

Loget, Philippe ^{[14
]}

Bonniere, Maryse

Starck, Lena ^{[15
]}

Tantau, Julia ^{[16
]}

Gentilin, Barbara ^{[8
]}

Majore, Silvia ^{[17
]}

Swistun, Dominika ^{[18
]}

Flori, Elizabeth ^{[19
]}

Lalatta, Faustina ^{[8
]}

Pantaleoni, Chiara ^{[11
]}

Penzien, Johannes ^{[20
]}

Grammatico, Paola ^{[17
]}

Dallapiccola, Bruno ^{[9
]}

Gleeson, Joseph G. ^{[18
]}

Attie-Bitach, Tania ^{[5
,6
,7
]}

Valente, Enza Maria ^{[1
,2
,21
]}

机构：

[1] CSS Mendel Inst, Neurogenet Unit, I-00198 Rome, Italy

[2] Casa Sollievo Sofferenza Hosp, San Giovanni Rotondo, Italy

[3] Univ G dAnnunzio, CeSI, Aging Res Ctr, Chieti, Italy

[4] Univ G dAnnunzio, Dept Biomed Sci, Chieti, Italy

[5] Hop Necker Enfants Malad, INSERM, U781, Paris 5, France

[6] Univ Paris 05, Paris 5, France

[7] Hop Necker Enfants Malad, APHP, Dept Genet, Paris, France

[8] Fdn IRCCS Osped Maggiore Policlin Mangiagalli & R, Milan, Italy

[9] IRCCS Osped Pediat Bambino Gesu, Rome, Italy

[10] Childrens Univ Hosp, Dept Neurol, Zurich, Switzerland

[11] Carlo Besta Neurol Inst Fdn, Div Neurol Sviluppo, Milan, Italy

[12] PO Giovanni XXII AOU Policlin Consorziale, UO Metab Dis Med Genet, Bari, Italy

[13] CHI Poissy, Serv Anat & Cytol Pathol, St Germain En Laye, France

[14] Cabinet Anat & Cytol Pathol Richier, Rennes, France

[15] Karolinska Inst, Sachs Childrens Hosp, Stockholm, Sweden

[16] Hop St Vincent de Paul, AP HP, Serv Anatomopathol, F-75674 Paris, France

[17] Sapienza Univ, Dept Expt Med, S Camillo Forlanini Hosp, Rome, Italy

[18] Univ Calif San Diego, Howard Hughes Med Inst, Neurogenet Lab, Dept Neurosci, La Jolla, CA 92093 USA

[19] Hop Univ Strasbourg, Serv Cytogenet Federat Genet, Strasbourg, France

[20] Childrens Hosp, Augsburg, Germany

[21] Univ Messina, Dept Med & Surg Pediat Sci, Messina, Italy

来源：

HUMAN MUTATION | 2010年 / 31卷 / 05期

关键词：

TMEM67; MKS3; Joubert syndrome; Meckel syndrome; congenital hepatic fibrosis; COACH syndrome; GRUBER-SYNDROME; JOUBERT-SYNDROME; PRIMARY CILIUM; CILIARY; MKS1; NEPHRONOPHTHISIS; DEFECTS; LIVER;

D O I：

10.1002/humu.21239

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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. (C) 2010 Wiley-Liss, Inc.

引用

页码：E1319 / E1331

页数：13

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