MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome

Kyttälä, Mira; Tallila, Jonna; Salonen, Riitta; Kopra, Outi; Kohlschmidt, Nicolai; Paavola–Sakki, Paulina; Peltonen, Leena; Kestilä, Marjo

doi:10.1038/ng1714

Cited by 227 publications

(186 citation statements)

References 15 publications

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“…OFD1 encodes a protein localizing to the nucleus and the basal body of the cilia (Romio et al, 2004) and an engineered null allele in mouse reveals a role for Ofd1 in limb, neural tube, craniofacial, and L-R patterning; indeed Ofd1 is required for normal nodal cilia formation (Ferrante et al, 2006). The MKS1 gene has also been implicated in ciliary function (Kyttala et al, 2006). These data support a role for cilia in the patterning events associated with the gasping mutants.…”

Section: Human Syndromes Show Gasping-like Featuresmentioning

confidence: 90%

Mouse mutagenesis identifies novel roles for left–right patterning genes in pulmonary, craniofacial, ocular, and limb development

Ермаков

Stevens

Whitehill

et al. 2009

Developmental Dynamics

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Vertebrate organs show consistent left-right (L-R) asymmetry in placement and patterning. To identify genes involved in this process we performed an ENU-based genetic screen. Of 135 lines analyzed 11 showed clear single gene defects affecting L-R patterning, including 3 new alleles of known L-R genes and mutants in novel L-R loci. We identified six lines (termed "gasping") that, in addition to abnormal L-R patterning and associated cardiovascular defects, had complex phenotypes including pulmonary agenesis, exencephaly, polydactyly, ocular and craniofacial malformations. These complex abnormalities are present in certain human disease syndromes (e.g., HYLS, SRPS, VACTERL). Gasping embryos also show defects in ciliogenesis, suggesting a role for cilia in these human congenital malformation syndromes. Our results indicate that genes controlling ciliogenesis and left-right asymmetry have, in addition to their known roles in cardiac patterning, major and unexpected roles in pulmonary, craniofacial, ocular and limb development with implications for human congenital malformation syndromes. Developmental Dynamics 238:581-594, 2009.

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Section: Human Syndromes Show Gasping-like Featuresmentioning

confidence: 90%

Mouse mutagenesis identifies novel roles for left–right patterning genes in pulmonary, craniofacial, ocular, and limb development

Ермаков

Stevens

Whitehill

et al. 2009

Developmental Dynamics

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“…2, 3 Our understanding of MKS pathogenesis has improved greatly over the past few years since it was first revealed that MKS1, the first gene found to be mutated in MKS, encodes a ciliary protein. 4 Subsequently, nine additional genes have been identified, all similarly encoding ciliary proteins (TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9) and B9D2 (MKS10)). [4][5][6][7][8][9][10][11][12][13][14] The finding that defective ciliary biology is the core molecular pathology of MKS made it possible to dissect the pathogenesis of each of its manifestations.…”

Section: Introductionmentioning

confidence: 99%

“…4 Subsequently, nine additional genes have been identified, all similarly encoding ciliary proteins (TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9) and B9D2 (MKS10)). [4][5][6][7][8][9][10][11][12][13][14] The finding that defective ciliary biology is the core molecular pathology of MKS made it possible to dissect the pathogenesis of each of its manifestations. For instance, the primary cilium plays a critical role in SHH signaling that controls anteriorposterior and dorsal-ventral patterning of the developing limb buds and neural tube, respectively, thus explaining the polydactyly and neural tube defects that characterize MKS at the molecular level.…”

Section: Introductionmentioning

confidence: 99%

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

et al. 2012

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Meckel-Gruber syndrome (MKS, OMIM #249000) is a multiple congenital malformation syndrome that represents the severe end of the ciliopathy phenotypic spectrum. Despite the relatively common occurrence of this syndrome among Arabs, little is known about its genetic architecture in this population. This is a series of 18 Arab families with MKS, who were evaluated clinically and studied using autozygome-guided mutation analysis and exome sequencing. We show that autozygome-guided candidate gene analysis identified the underlying mutation in the majority (n ¼ 12, 71%). Exome sequencing revealed a likely pathogenic mutation in three novel candidate MKS disease genes. These include C5orf42, Ellis-van-Creveld disease gene EVC2 and SEC8 (also known as EXOC4), which encodes an exocyst protein with an established role in ciliogenesis. This is the largest and most comprehensive genomic study on MKS in Arabs and the results, in addition to revealing genetic and allelic heterogeneity, suggest that previously reported disease genes and the novel candidates uncovered by this study account for the overwhelming majority of MKS patients in our population.

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“…Recently, two genes were identified: MKS1 (MIM# 609883) in Finnish and Caucasian kindreds and MKS3 (MIM# 609884) in Omani and Pakistani families [Kyttälä et al, 2006;Smith et al, 2006]. Only four different MKS1 mutations have been described so far [Kyttälä et al, 2006;Dawe et al, in press]. Two of them were exonic frameshifting mutations [a 5-bp insertion c.51_55ins (p.Pro17fs) and a 4-bp duplication c.1448_1451dup (p.Thr485fs)] and two were splice mutations affecting the canonic donor splice site of intron 1 (c.80+2T>C) or the splice branching site of intron 15 (c.1408-7_35del).…”

Section: Introductionmentioning

confidence: 99%

Aberrant splicing is a common mutational mechanism inMKS1, a key player in Meckel-Gruber syndrome

et al. 2007

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Meckel-Gruber syndrome (MKS) is an autosomal recessive, usually lethal multisystemic disorder characterized by early developmental anomalies of the central nervous system, cystic kidney dysplasia, hepatobiliary ductal plate malformation, and postaxial polydactyly. 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"). We performed linkage analysis for MKS1-3 in 14 consanguineous and/or multiplex families of different ethnic origins with histologic diagnosis and at least three classic MKS manifestations in each kindred. Unexpectedly, only five families were linked to any of the known MKS loci, clearly indicating further locus heterogeneity. All five families showed homozygosity for MKS1 and, intriguingly, were of non-Caucasian origin. MKS1 sequencing revealed no mutation in two of these pedigrees, whereas different, novel splicing defects were identified in the three other families and an additional sporadic German patient. Given that all of our mutations and two of the in total four known MKS1 changes cause aberrant splicing (while the other two known mutations were frameshift mutations), we hypothesize that splicing defects are a crucial mutational mechanism in MKS1 which apparently is one of the main loci and key players in MKS. Our results indicate that MKS1 mutations are not restricted to the Caucasian gene pool and suggest further genetic heterogeneity for MKS. Overall, our data have immediate implications for genetic counselling and testing approaches in MKS.

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MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome

Cited by 227 publications

References 15 publications

Mouse mutagenesis identifies novel roles for left–right patterning genes in pulmonary, craniofacial, ocular, and limb development

Mouse mutagenesis identifies novel roles for left–right patterning genes in pulmonary, craniofacial, ocular, and limb development

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

Aberrant splicing is a common mutational mechanism inMKS1, a key player in Meckel-Gruber syndrome

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