title: The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1.
abstract: 3-M syndrome is an autosomal-recessive primordial growth disorder characterized by significant intrauterine and postnatal growth restriction. Mutations in the CUL7 gene are known to cause 3-M syndrome. In 3-M syndrome patients that do not carry CUL7 mutations, we performed high-density genome-wide SNP mapping to identify a second locus at 2q35-q36.1. Further haplotype analysis revealed a 1.29 Mb interval in which the underlying gene is located and we subsequently discovered seven distinct null mutations from 10 families within the gene OBSL1. OBSL1 is a putative cytoskeletal adaptor protein that localizes to the nuclear envelope. We were also able to demonstrate that loss of OBSL1 leads to downregulation of CUL7, implying a role for OBSL1 in the maintenance of CUL7 protein levels and suggesting that both proteins are involved within the same molecular pathway.
authors.affiliation: Endocrine Sciences, Faculty of Medical & Human Sciences, University of Manchester, Manchester, UK.
authors.forename: Dan
authors.initials: D
authors.lastname: Hanson
authors.forename: Philip G
authors.initials: PG
authors.lastname: Murray
authors.forename: Amit
authors.initials: A
authors.lastname: Sud
authors.forename: Samia A
authors.initials: SA
authors.lastname: Temtamy
authors.forename: Mona
authors.initials: M
authors.lastname: Aglan
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Sue E
authors.initials: SE
authors.lastname: Holder
authors.forename: Jill
authors.initials: J
authors.lastname: Urquhart
authors.forename: Emma
authors.initials: E
authors.lastname: Hilton
authors.forename: Forbes D C
authors.initials: FD
authors.lastname: Manson
authors.forename: Peter
authors.initials: P
authors.lastname: Scambler
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Black
authors.forename: Peter E
authors.initials: PE
authors.lastname: Clayton
mesh_terms: D000293:Adolescent; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D044842:Cullin Proteins / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D003599:Cytoskeleton; D005260:Female; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D007223:Infant; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D034741:RNA, Small Interfering / Q000494:pharmacology; D013577:Syndrome; D054875:Ubiquitination
chemical_list: C506299:CUL7 protein, human; D044842:Cullin Proteins; D003598:Cytoskeletal Proteins; C522000:OBSL1 protein, human; D034741:RNA, Small Interfering