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

Overview

Journal Hum Mutat

Specialty Genetics

Date 2010 Mar 17

PMID 20232449

Citations 52

Authors

Miriam Iannicelli

Francesco Brancati

Soumaya Mougou-Zerelli

Annalisa Mazzotta

Sophie Thomas

Nadia Elkhartoufi

Lorena Travaglini

Celine Gomes

Gian Luigi Ardissino

Enrico Bertini

Eugen Boltshauser

Pierangela Castorina

Stefano DArrigo

Rita Fischetto

Brigitte Leroy

Philippe Loget

Maryse Bonniere

Lena Starck

Julia Tantau

Barbara Gentilin

Silvia Majore

Dominika Swistun

Elizabeth Flori

Faustina Lalatta

Chiara Pantaleoni

Johannes Penzien

Paola Grammatico

Bruno Dallapiccola

Joseph G Gleeson

Tania Attie-Bitach

Enza Maria Valente

Affiliations

Soon will be listed here.

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.

Citing Articles

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Two novel TMEM67 variations in a Chinese family with recurrent pregnancy loss: a case report.

Pang J, Kong F, Tang W, Xi H, Ma N, Sheng X BMC Med Genomics. 2024; 17(1):156.

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Nephronophthisis: a pathological and genetic perspective.

Wolf M, Bonsib S, Larsen C, Hildebrandt F Pediatr Nephrol. 2023; 39(7):1977-2000.

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A case of Joubert syndrome caused by novel compound heterozygous variants in the gene.

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