In two consanguineous families with classical MKS in which autozygome-guided sequencing of previously reported MKS genes was negative, we performed exome sequencing followed by autozygome filtration.
Here we show that loss of function of mouse Mks1 results in an accurate model of human MKS, with structural abnormalities in the neural tube, biliary duct, limb patterning, bone development and the kidney that mirror the human syndrome.
Here we report a cohort of 26 patients referred for genetic analysis of Joubert (JBTS) and Meckel-Gruber (MKS) syndromes, two clinically and genetically heterogeneous neurodevelopmental conditions that define a phenotypic spectrum, with MKS at the severe end.
In the case of prenatal ultrasound findings that are highly suggestive of MKS and a negative NGS MKS gene panel, WES should also be performed to not miss rare gene associations.
The exclusion of this and the other seven MKS genes in our collection of consanguineous Arab MKS families confirms the existence of two additional MKS loci.
The secondary aim was to screen for novel mutations in the coding sequence of the MKS1 gene of MKS fetuses and to obtain genotype-phenotype correlations where possible.
MKS is genetically heterogeneous with six known disease genes: MKS1, MKS2/TMEM216, MKS3/TMEM67, RPGRIP1L, CEP290, and CC2D2A with the encoded proteins all implicated in the correct function of primary cilia.
This novel model system offers insights into the role of MKS1 in Wnt signalling and proliferation, and the impact of deregulation of these processes on brain and kidney development in MKS, as well as expanding our understanding of the role of Mks1 in multiple signalling pathways.
The TZ is known to harbour two functional modules/complexes (Meckel syndrome [MKS] and Nephronophthisis [NPHP]) defined by genetic interaction, interdependent protein localisation (hierarchy), and proteomic studies.
We also examined the relationship between the MKS complex and IFT proteins by analyzing double mutant between Mks1 and a hypomorphic allele of the IFTB component Ift172.
In our patient, a next generation sequencing (NGS) approach revealed the following two variants of the MKS1 gene: first, a novel missense variant [ c.240G > T (p.Trp80Cys)], which affects a residue that is evolutionarily highly conserved in mammals and ciliates; second, a 29 bp deletion in intron 15 [c.1408-35_1408-7del29], a founder mutation, which in a homozygous state constitutes the major cause of MKS in Finland.
Our first results indicate that the MKS1 and MKS3 genes are each responsible for about 7% of MKS cases with various mutations in different populations.
Three MKS loci have been mapped and recently, two genes were identified: MKS1 on 17q22 in Caucasian kindreds and MKS3 on 8q22 in Omani and Pakistani families, putting MKS on the growing list of ciliary disorders ("ciliopathies").
The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway.