Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies.
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.
Iannicelli
Miriam
M
Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo and CSS-Mendel Institute, viale Regina Margherita 261, Rome, Italy.
Brancati
Francesco
F
Mougou-Zerelli
Soumaya
S
Mazzotta
Annalisa
A
Thomas
Sophie
S
Elkhartoufi
Nadia
N
Travaglini
Lorena
L
Gomes
Céline
C
Ardissino
Gian Luigi
GL
Bertini
Enrico
E
Boltshauser
Eugen
E
Castorina
Pierangela
P
D'Arrigo
Stefano
S
Fischetto
Rita
R
Leroy
Brigitte
B
Loget
Philippe
P
Bonnière
Maryse
M
Starck
Lena
L
Tantau
Julia
J
Gentilin
Barbara
B
Majore
Silvia
S
Swistun
Dominika
D
Flori
Elizabeth
E
Lalatta
Faustina
F
Pantaleoni
Chiara
C
Penzien
Johannes
J
Grammatico
Paola
P
Dallapiccola
Bruno
B
Gleeson
Joseph G
JG
Attie-Bitach
Tania
T
Valente
Enza Maria
EM
D000015:Abnormalities, Multiple / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011247:Pregnancy; D011296:Prenatal Diagnosis
D008565:Membrane Proteins; C468846:TMEM67 protein, human