TY - JOUR
T1 - Homozygous and compound heterozygous mutations in ZMPSTE24 cause the laminopathy restrictive dermopathy
AU - Moulson, Casey L.
AU - Go, Gloriosa
AU - Gardner, Jennifer M.
AU - Van Der Wal, Allard C.
AU - Smitt, J. Henk Sillevis
AU - Van Hagen, Johanna M.
AU - Miner, Jeffrey H.
N1 - Funding Information:
We are extremely grateful to the families who participated in this study and to the referring physicians, scientists, and genetic counselors for their invaluable contributions. We thank The Laboratory of Developmental Biology at the Univerisity of Washington in Seattle, supported by National Institutes of Health grant R24HD000836, for supplying human fetal liver tissue, and Edward Fox and the Dana-Farber Cancer Institute Microarray Core for performing SNP genotyping; the Washington University School of Medicine Division of Human Genetics Genotyping Core for facilitating DHPLC analysis; Martin Pollak and Alan Beggs for advice; Phillip Stahl and Didier Hodzic for use of the confocal microscope; and Paul Goodfellow for helpful suggestions and comments on the manuscript. This work was funded by National Institutes of Health grant R01AR049269 to JHM.
PY - 2005/11
Y1 - 2005/11
N2 - Restrictive dermopathy (RD) is a lethal human genetic disorder characterized by very tight, thin, easily eroded skin, rocker bottom feet, and joint contractures. This disease was recently reported to be associated with a single heterozygous mutation in ZMPSTE24 and hypothesized to be a digenic disorder (Navarro et al, Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy. Hum Mol Genet 13:2493-2503, 2004). ZMPSTE24 encodes an enzyme necessary for the correct processing and maturation of lamin A, an intermediate filament component of the nuclear envelope. Here we present four unrelated patients with homozygous mutations in ZMPSTE24 and a fifth patient with compound heterozygous mutations in ZMPSTE24. Two of the three different mutations we found are novel, and all are single base insertions that result in messenger RNA frameshifts. As a consequence of the presumed lack of ZMPSTE24 activity, prelamin A, the unprocessed toxic form of lamin A, was detected in the nuclei of both cultured cells and tissue from RD patients, but not in control nuclei. Abnormally aggregated lamin A/C was also observed. These results indicate that RD is an autosomal recessive laminopathy caused by inactivating ZMPSTE24 mutations that result in defective processing and nuclear accumulation of prelamin A.
AB - Restrictive dermopathy (RD) is a lethal human genetic disorder characterized by very tight, thin, easily eroded skin, rocker bottom feet, and joint contractures. This disease was recently reported to be associated with a single heterozygous mutation in ZMPSTE24 and hypothesized to be a digenic disorder (Navarro et al, Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy. Hum Mol Genet 13:2493-2503, 2004). ZMPSTE24 encodes an enzyme necessary for the correct processing and maturation of lamin A, an intermediate filament component of the nuclear envelope. Here we present four unrelated patients with homozygous mutations in ZMPSTE24 and a fifth patient with compound heterozygous mutations in ZMPSTE24. Two of the three different mutations we found are novel, and all are single base insertions that result in messenger RNA frameshifts. As a consequence of the presumed lack of ZMPSTE24 activity, prelamin A, the unprocessed toxic form of lamin A, was detected in the nuclei of both cultured cells and tissue from RD patients, but not in control nuclei. Abnormally aggregated lamin A/C was also observed. These results indicate that RD is an autosomal recessive laminopathy caused by inactivating ZMPSTE24 mutations that result in defective processing and nuclear accumulation of prelamin A.
KW - FATP4 protein
KW - Lamin A
KW - Nuclear envelope
KW - STE24 protein
UR - http://www.scopus.com/inward/record.url?scp=30844451421&partnerID=8YFLogxK
U2 - 10.1111/j.0022-202X.2005.23846.x
DO - 10.1111/j.0022-202X.2005.23846.x
M3 - Article
C2 - 16297189
AN - SCOPUS:30844451421
SN - 0022-202X
VL - 125
SP - 913
EP - 919
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 5
ER -