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.
Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo and CSS-Mendel Institute, viale Regina Margherita 261, Rome, Italy.
Miriam
M
Iannicelli
Francesco
F
Brancati
Soumaya
S
Mougou-Zerelli
Annalisa
A
Mazzotta
Sophie
S
Thomas
Nadia
N
Elkhartoufi
Lorena
L
Travaglini
Céline
C
Gomes
Gian Luigi
GL
Ardissino
Enrico
E
Bertini
Eugen
E
Boltshauser
Pierangela
P
Castorina
Stefano
S
D'Arrigo
Rita
R
Fischetto
Brigitte
B
Leroy
Philippe
P
Loget
Maryse
M
Bonnière
Lena
L
Starck
Julia
J
Tantau
Barbara
B
Gentilin
Silvia
S
Majore
Dominika
D
Swistun
Elizabeth
E
Flori
Faustina
F
Lalatta
Chiara
C
Pantaleoni
Johannes
J
Penzien
Paola
P
Grammatico
Bruno
B
Dallapiccola
Joseph G
JG
Gleeson
Tania
T
Attie-Bitach
Enza Maria
EM
Valente
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