The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1.
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.
Hanson
Dan
D
Endocrine Sciences, Faculty of Medical & Human Sciences, University of Manchester, Manchester, UK.
Murray
Philip G
PG
Sud
Amit
A
Temtamy
Samia A
SA
Aglan
Mona
M
Superti-Furga
Andrea
A
Holder
Sue E
SE
Urquhart
Jill
J
Hilton
Emma
E
Manson
Forbes D C
FD
Scambler
Peter
P
Black
Graeme C M
GC
Clayton
Peter E
PE
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
C506299:CUL7 protein, human; D044842:Cullin Proteins; D003598:Cytoskeletal Proteins; C522000:OBSL1 protein, human; D034741:RNA, Small Interfering