Mutations in ANAPC1, Encoding a Scaffold Subunit of the Anaphase-Promoting Complex, Cause Rothmund-Thomson Syndrome Type 1

Abstract

Rothmund-Thomson syndrome (RTS) is an autosomal-recessive disorder characterized by poikiloderma, sparse hair, short stature, and skeletal anomalies. Type 2 RTS, which is defined by the presence of bi-allelic mutations in RECQL4, is characterized by increased cancer susceptibility and skeletal anomalies, whereas the genetic basis of RTS type 1, which is associated with juvenile cataracts, is unknown. We studied ten individuals, from seven families, who had RTS type 1 and identified a deep intronic splicing mutation of the ANAPC1 gene, a component of the anaphase-promoting complex/cyclosome (APC/C), in all affected individuals, either in the homozygous state or in trans with another mutation. Fibroblast studies showed that the intronic mutation causes the activation of a 95 bp pseudoexon, leading to mRNAs with premature termination codons and nonsense-mediated decay, decreased ANAPC1 protein levels, and prolongation of interphase. Interestingly, mice that were heterozygous for a knockout mutation have an increased incidence of cataracts. Our results demonstrate that deficiency in the APC/C is a cause of RTS type 1 and suggest a possible link between the APC/C and RECQL4 helicase because both proteins are involved in DNA repair and replication.

Premature aging disorders: A clinical and genetic compendium

“…Rothmund‐Thomson syndrome is subdivided into two different types. The majority of more than 300 reported cases belong to Rothmund‐Thomson syndrome type 2, which is due to biallelic truncating and missense mutations in RECQL4 gene 130‐132 and is associated more often with increased cancer risk and skeletal anomalies 133 . RECQL4 is coding for a DNA helicase of the RecQ family and is linked to genomic instability, carcinogenesis and aging processes 134 .…”

“…RECQL4 is coding for a DNA helicase of the RecQ family and is linked to genomic instability, carcinogenesis and aging processes 134 . Biallelic mutations in RECQL4 have also been identified in patients with Rapadilino syndrome (MIM #266280) and Baller‐Gerold syndrome (MIM #218600), 135 which share clinical features with Rothmund‐Thomson syndrome such as growth retardation, skeletal anomalies and increased cancer risk 133 . Recently, biallelic mutations in the ANAPC1 gene were described as cause of Rothmund‐Thomson syndrome type 1, which is characterized by the presence of juvenile cataracts.…”

“…Recently, biallelic mutations in the ANAPC1 gene were described as cause of Rothmund‐Thomson syndrome type 1, which is characterized by the presence of juvenile cataracts. All 10 patients reported so far exhibit a deep intronic splicing mutation in ANAPC1 either in homozygous state or compound heterozygous with another truncating mutation 133 . ANAPC1 belongs to an anaphase‐promoting complex/cyclosome that is known to be involved in DNA replication and repair, cell differentiation, cell senescence metabolism and neuronal function 136 …”

Congenital Diseases of DNA Replication: Clinical Phenotypes and Molecular Mechanisms

“…It is important to note that, as with many diseases that were first described based on clinical characteristics, not all individuals with BGS and RTS have the same genetic cause. Ten percent of individuals clinically diagnosed with RTS have mutations in anaphase promoting complex subunit 1 ( ANAPC1 ) and 30% do not have a known genetic cause [ 195 , 196 ]. Similarly, patients with BGS carry mutations in twist family BHLH transcription factor 1 ( TWIST1 ), defects in which are known to cause craniosynostosis [ 170 ].…”

In silicoAPC/C substrate discovery reveals cell cycle degradation of chromatin regulators including UHRF1

“…In addition, the APC/C subunit Cdc27 is mutated in cancer and associated with aneuploidy (12). APC/C is also linked to inherited disorders that give a range of disease phenotypes, including microcephaly, cancer predisposition, and skeletal abnormalities (13,14).…”