Ciliary abnormalities due to defects in the retrograde transport protein DYNC2H1 in short-rib polydactyly syndrome.
The short-rib polydactyly (SRP) syndromes are a heterogeneous group of perinatal lethal skeletal disorders with polydactyly and multisystem organ abnormalities. Homozygosity by descent mapping in a consanguineous SRP family identified a genomic region that contained DYNC2H1, a cytoplasmic dynein involved in retrograde transport in the cilium. Affected individuals in the family were homozygous for an exon 12 missense mutation that predicted the amino acid substitution R587C. Compound heterozygosity for one missense and one null mutation was identified in two additional nonconsanguineous SRP families. Cultured chondrocytes from affected individuals showed morphologically abnormal, shortened cilia. In addition, the chondrocytes showed abnormal cytoskeletal microtubule architecture, implicating an altered microtubule network as part of the disease process. These findings establish SRP as a cilia disorder and demonstrate that DYNC2H1 is essential for skeletogenesis and growth.
Merrill
Amy E
AE
Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Merriman
Barry
B
Farrington-Rock
Claire
C
Camacho
Natalia
N
Sebald
Eiman T
ET
Funari
Vincent A
VA
Schibler
Matthew J
MJ
Firestein
Marc H
MH
Cohn
Zachary A
ZA
Priore
Mary Ann
MA
Thompson
Alicia K
AK
Rimoin
David L
DL
Nelson
Stanley F
SF
Cohn
Daniel H
DH
Krakow
Deborah
D
D001483:Base Sequence; D002478:Cells, Cultured; D019902:Chondrocytes / Q000473:pathology; D002923:Cilia / Q000473:pathology*; D018389:Codon, Nonsense; D003241:Consanguinity; D056445:Cytoplasmic Dyneins; D017931:DNA Primers / Q000235:genetics; D004398:Dyneins / Q000235:genetics* / Q000502:physiology; D005260:Female; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D011247:Pregnancy; D011859:Radiography; D012779:Short Rib-Polydactyly Syndrome / Q000000981:diagnostic imaging / Q000196:embryology / Q000235:genetics*
D018389:Codon, Nonsense; D017931:DNA Primers; C099883:DYNC2H1 protein, human; D056445:Cytoplasmic Dyneins; D004398:Dyneins