title: Identification of a novel MKS locus defined by TMEM107 mutation.
abstract: Meckel-Gruber syndrome (MKS) is a perinatally lethal disorder characterized by the triad of occipital encephalocele, polydactyly and polycystic kidneys. Typical of other disorders related to defective primary cilium (ciliopathies), MKS is genetically heterogeneous with mutations in a dozen genes to date known to cause the disease. In an ongoing effort to characterize MKS clinically and genetically, we implemented a gene panel and next-generation sequencing approach to identify the causal mutation in 25 MKS families. Of the three families that did not harbor an identifiable causal mutation by this approach, two mapped to a novel disease locus in which whole-exome sequencing revealed the likely causal mutation as a homozygous splicing variant in TMEM107, which we confirm leads to aberrant splicing and nonsense-mediated decay. TMEM107 had been independently identified in two mouse models as a cilia-related protein and mutant mice display typical ciliopathy phenotypes. Our analysis of patient fibroblasts shows marked ciliogenesis defect with an accompanying perturbation of sonic hedgehog signaling, highly concordant with the cellular phenotype in Tmem107 mutants. This study shows that known MKS loci account for the overwhelming majority of MKS cases but additional loci exist including MKS13 caused by TMEM107 mutation.
authors.affiliation: Department of Genetics and.
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.affiliation: Department of Genetics and.
authors.forename: Agaadir
authors.initials: A
authors.lastname: Almoisheer
authors.affiliation: Department of Pediatric Subspecialty, Children's Specialized Hospital, King Fahad Medical City, Riyadh 59046, Saudi Arabia.
authors.forename: Eissa
authors.initials: E
authors.lastname: Faqeih
authors.affiliation: Depatment of Obstetrics and Gynecology, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Zainab
authors.initials: Z
authors.lastname: Babay
authors.affiliation: Department of Genetics and Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: Dorota
authors.initials: D
authors.lastname: Monies
authors.affiliation: Department of Genetics and Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: Nada
authors.initials: N
authors.lastname: Tassan
authors.affiliation: Department of Genetics and Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abouelhoda
authors.affiliation: Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Wesam
authors.initials: W
authors.lastname: Kurdi
authors.affiliation: Department of Obstetrics and Gynecology and.
authors.forename: Elham
authors.initials: E
authors.lastname: Al Mardawi
authors.affiliation: Department of Obstetrics and Gynecology and Department of Obstetrics and Gynecology, Menoufiya University, Menoufiya, Egypt.
authors.forename: Mohamed M I
authors.initials: MM
authors.lastname: Khalil
authors.affiliation: Department of Pediatrics, Security Forces Hospital Program, Riyadh, Saudi Arabia.
authors.forename: Mohammed Zain
authors.initials: MZ
authors.lastname: Seidahmed
authors.affiliation: Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Maha
authors.initials: M
authors.lastname: Alnemer
authors.affiliation: Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Nada
authors.initials: N
authors.lastname: Alsahan
authors.affiliation: Department of Medical Genetics, King Fahad General Hospital, Jeddah, Saudi Arabia.
authors.forename: Samira
authors.initials: S
authors.lastname: Sogaty
authors.affiliation: Department of Pediatrics, Prince Sultan Military Medical City, Riyadh 11159, Saudi Arabia.
authors.forename: Amal
authors.initials: A
authors.lastname: Alhashem
authors.affiliation: Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India.
authors.forename: Ankur
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India.
authors.forename: Manisha
authors.initials: M
authors.lastname: Goyal
authors.affiliation: Department of Pediatrics Genetic & Research Laboratory, Maulana Azad Medical College, New Delhi, India and.
authors.forename: Seema
authors.initials: S
authors.lastname: Kapoor
authors.affiliation: Department of Genetics and.
authors.forename: Rana
authors.initials: R
authors.lastname: Alomar
authors.affiliation: Department of Genetics and.
authors.forename: Niema
authors.initials: N
authors.lastname: Ibrahim
authors.affiliation: Department of Genetics and Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia, Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia falkuraya@kfshrc.edu.sa alkuraya@outlook.com.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000483:Alleles; D002923:Cilia / Q000235:genetics / Q000378:metabolism; D002925:Ciliary Motility Disorders / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004677:Encephalocele / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018740:Genetic Heterogeneity; D056426:Genetic Loci; D005838:Genotype; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D007690:Polycystic Kidney Diseases / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D012174:Retinitis Pigmentosa; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D008565:Membrane Proteins; C000607975:TMEM107 protein, human