TY - JOUR
T1 - Defective DNA Polymerase α-Primase Leads to X-Linked Intellectual Disability Associated with Severe Growth Retardation, Microcephaly, and Hypogonadism
AU - Van Esch, Hilde
AU - Colnaghi, Rita
AU - Freson, Kathleen
AU - Starokadomskyy, Petro
AU - Zankl, Andreas
AU - Backx, Liesbeth
AU - Abramowicz, Iga
AU - Outwin, Emily
AU - Rohena, Luis
AU - Faulkner, Claire
AU - Leong, Gary M.
AU - Newbury-Ecob, Ruth A.
AU - Challis, Rachel C.
AU - Õunap, Katrin
AU - Jaeken, Jacques
AU - Seuntjens, Eve
AU - Devriendt, Koen
AU - Burstein, Ezra
AU - Low, Karen J.
AU - O'Driscoll, Mark
N1 - Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
PY - 2019/5/2
Y1 - 2019/5/2
N2 -
Replicating the human genome efficiently and accurately is a daunting challenge involving the duplication of upward of three billion base pairs. At the core of the complex machinery that achieves this task are three members of the B family of DNA polymerases: DNA polymerases α, δ, and ε. Collectively these multimeric polymerases ensure DNA replication proceeds at optimal rates approaching 2 × 10
3
nucleotides/min with an error rate of less than one per million nucleotides polymerized. The majority of DNA replication of undamaged DNA is conducted by DNA polymerases δ and ε. The DNA polymerase α-primase complex performs limited synthesis to initiate the replication process, along with Okazaki-fragment synthesis on the discontinuous lagging strand. An increasing number of human disorders caused by defects in different components of the DNA-replication apparatus have been described to date. These are clinically diverse and involve a wide range of features, including variable combinations of growth delay, immunodeficiency, endocrine insufficiencies, lipodystrophy, and cancer predisposition. Here, by using various complementary approaches, including classical linkage analysis, targeted next-generation sequencing, and whole-exome sequencing, we describe distinct missense and splice-impacting mutations in POLA1 in five unrelated families presenting with an X-linked syndrome involving intellectual disability, proportionate short stature, microcephaly, and hypogonadism. POLA1 encodes the p180 catalytic subunit of DNA polymerase α-primase. A range of replicative impairments could be demonstrated in lymphoblastoid cell lines derived from affected individuals. Our findings describe the presentation of pathogenic mutations in a catalytic component of a B family DNA polymerase member, DNA polymerase α.
AB -
Replicating the human genome efficiently and accurately is a daunting challenge involving the duplication of upward of three billion base pairs. At the core of the complex machinery that achieves this task are three members of the B family of DNA polymerases: DNA polymerases α, δ, and ε. Collectively these multimeric polymerases ensure DNA replication proceeds at optimal rates approaching 2 × 10
3
nucleotides/min with an error rate of less than one per million nucleotides polymerized. The majority of DNA replication of undamaged DNA is conducted by DNA polymerases δ and ε. The DNA polymerase α-primase complex performs limited synthesis to initiate the replication process, along with Okazaki-fragment synthesis on the discontinuous lagging strand. An increasing number of human disorders caused by defects in different components of the DNA-replication apparatus have been described to date. These are clinically diverse and involve a wide range of features, including variable combinations of growth delay, immunodeficiency, endocrine insufficiencies, lipodystrophy, and cancer predisposition. Here, by using various complementary approaches, including classical linkage analysis, targeted next-generation sequencing, and whole-exome sequencing, we describe distinct missense and splice-impacting mutations in POLA1 in five unrelated families presenting with an X-linked syndrome involving intellectual disability, proportionate short stature, microcephaly, and hypogonadism. POLA1 encodes the p180 catalytic subunit of DNA polymerase α-primase. A range of replicative impairments could be demonstrated in lymphoblastoid cell lines derived from affected individuals. Our findings describe the presentation of pathogenic mutations in a catalytic component of a B family DNA polymerase member, DNA polymerase α.
KW - growth retardation
KW - intellectual disability
KW - microcephaly
KW - POLA1
KW - polymerase alpha
KW - X-linked
UR - http://www.scopus.com/inward/record.url?scp=85064952832&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2019.03.006
DO - 10.1016/j.ajhg.2019.03.006
M3 - Article (Academic Journal)
C2 - 31006512
AN - SCOPUS:85064952832
SN - 0002-9297
VL - 104
SP - 957
EP - 967
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -