NovelTMEM67mutations and genotype-phenotype correlates in meckelin-related ciliopathies

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. ©2010Wiley-Liss, Inc.

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

“…The INPP5E phenotypic spectrum appears to largely overlap with that related to AHI1 mutations; 18 conversely, none of the INPP5E-mutated patients presented polydactyly or encephalocele, two features that are often associated with mutations in genes also causative of MKS, such as TMEM216, CEP290, TMEM67 or RPGRIP1L. 5,[19][20][21] In one patient with pure JS (COR28), only a single heterozygous INPP5E mutation could be detected, despite complete sequencing of the coding regions and canonical splice sites, and search for genomic rearrangements. Although we cannot exclude the possibility that a second pathogenic mutation resides within intronic or regulatory regions of the gene, it is also plausible that the identified change could act as a genetic modifier of the clinical phenotype in an oligogenic context, and that digenic mutations may reside in another gene.…”

Missense variants in TMEM67 in a patient with Joubert syndrome

“…This results in a change from the amino acid serine at position 312 to proline: c.934T>C; p.(Ser312Pro). Although this variant is not in a known functional domain, other patients with Joubert syndrome have been found to carry missense mutations at nearby nucleotide positions 903 and 986 (c.903C>G (p.Asp301Glu)) and (c.986A>C (p.Lys329Thr)) 12, 16. This variant is a novel missense change that is not present in any population databases (ACMG PM2).…”

“…This results in a change from the amino acid cysteine at position 173 to an arginine: c.517T>C; p.(Cys173Arg). This amino acid change falls in a cysteine‐rich domain in TMEM67 that spans amino acids 50‐18712 and mediates signaling through WNT5A interactions 8, 14. Mutations in similar regions in TMEM67 have been found in patients with Joubert syndrome and Joubert syndrome with the COACH (cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis) phenotype.…”

“…TMEM67/MKS3 is found on chromosome 8 (8q22.1) and encodes a 955‐amino acid seven‐transmembrane receptor protein that is thought to regulate cilia function and mutations in TMEM67/MKS3 can also cause Meckel‐Gruber syndrome (MKS), another autosomal recessive ciliopathy that is associated with renal cystic disease 8, 9, 10, 11. Although mutations in TMEM67/MKS3 are causative for both syndromes (accounting for 9% of JSRD cases and 16% of MKS cases), a correlation between missense mutations in exons 8‐15, particularly in combination with truncating mutations, and Meckel‐Gruber syndrome has been identified 7, 12…”

Clinical utility gene card for: Meckel syndrome

“…So far, 37 different mutations described in patients with the Meckel-Gruber phenotype (5 nonsense, 17 missense, 7 canonical splice-site mutations, 7 small deletions/insertions/duplications, and 1 gross deletion described at genomic DNA level encompassing exons 17-21). 3,13,14 CEP290/MKS4: Recurrent mutation c.1219_1220del p.Met407fs in several families. A total of 13 different mutations described so far in patients with the Meckel-Gruber phenotype (five nonsense, two canonical splicesite mutations, and six small deletions/insertions/duplications).…”