TY - JOUR
T1 - Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1
AU - Mazor, Masha
AU - Alkrinawi, Soliman
AU - Chalifa-Caspi, Vered
AU - Manor, Esther
AU - Sheffield, Val C.
AU - Aviram, Micha
AU - Parvari, Ruti
PY - 2011/5/13
Y1 - 2011/5/13
N2 - In primary ciliary dyskinesia (PCD), genetic defects affecting motility of cilia and flagella cause chronic destructive airway disease, randomization of left-right body asymmetry, and, frequently, male infertility. The most frequent defects involve outer and inner dynein arms (ODAs and IDAs) that are large multiprotein complexes responsible for cilia-beat generation and regulation, respectively. Although it has long been suspected that mutations in DNAL1 encoding the ODA light chain1 might cause PCD such mutations were not found. We demonstrate here that a homozygous point mutation in this gene is associated with PCD with absent or markedly shortened ODA. The mutation (NM-031427.3: c.449A>G; p.Asn150Ser) changes the Asn at position150, which is critical for the proper tight turn between the β strand and the α helix of the leucine-rich repeat in the hydrophobic face that connects to the dynein heavy chain. The mutation reduces the stability of the axonemal dynein light chain 1 and damages its interactions with dynein heavy chain and with tubulin. This study adds another important component to understanding the types of mutations that cause PCD and provides clinical information regarding a specific mutation in a gene not yet known to be associated with PCD.
AB - In primary ciliary dyskinesia (PCD), genetic defects affecting motility of cilia and flagella cause chronic destructive airway disease, randomization of left-right body asymmetry, and, frequently, male infertility. The most frequent defects involve outer and inner dynein arms (ODAs and IDAs) that are large multiprotein complexes responsible for cilia-beat generation and regulation, respectively. Although it has long been suspected that mutations in DNAL1 encoding the ODA light chain1 might cause PCD such mutations were not found. We demonstrate here that a homozygous point mutation in this gene is associated with PCD with absent or markedly shortened ODA. The mutation (NM-031427.3: c.449A>G; p.Asn150Ser) changes the Asn at position150, which is critical for the proper tight turn between the β strand and the α helix of the leucine-rich repeat in the hydrophobic face that connects to the dynein heavy chain. The mutation reduces the stability of the axonemal dynein light chain 1 and damages its interactions with dynein heavy chain and with tubulin. This study adds another important component to understanding the types of mutations that cause PCD and provides clinical information regarding a specific mutation in a gene not yet known to be associated with PCD.
UR - http://www.scopus.com/inward/record.url?scp=79955856801&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2011.03.018
DO - 10.1016/j.ajhg.2011.03.018
M3 - Article
C2 - 21496787
AN - SCOPUS:79955856801
SN - 0002-9297
VL - 88
SP - 599
EP - 607
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -