ロスムンド・トムソン症候群

RecQ helicases are a conserved family of DNA-unwinding enzymes that play a key role in maintaining genomic stability by participating in DNA damage repair, recombination, replication, and telomere homeostasis. Five RecQ helicases are known in humans: BLM (the Bloom syndrome protein), WRN (Werner syndrome helicase), RECQL4, RECQL1, and RECQL5. All members of the RecQ family possess 3' → 5' helicase activity and are capable of unwinding DNA, including its complex secondary structures, in the 3'-to-5' direction by using the energy of ATP hydrolysis. WRN is unique among RecQ helicases in possessing additional 3' → 5' exonuclease activity, which expands its functionality in maintaining genomic stability. Mutations of the RecQ helicase genes lead to Werner, Bloom, and Rothmund-Thomson syndromes and are associated with a predisposition to cancer and premature aging. The enzymes consequently attract significant interest of the scientific community. Many viruses rely on host cell replication and repair mechanisms for their reproduction, and RecQ helicases may therefore influence the development of viral infections. The review discusses the role of RecQ helicases in replication of various viruses, including socially significant ones, such as the human immunodeficiency virus, herpes simplex virus, Epstein-Barr virus, hepatitis C virus, and others.

BACKGROUND: Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive genodermatosis typically associated with mutations in the RECQL4 gene. However, some clinically diagnosed cases lack such variants, indicating genetic heterogeneity. ANAPC1, encoding a subunit of the anaphase-promoting complex (APC/C), has been implicated in RTS type 1, but its involvement in hair disorders remains unexplored. CASE PRESENTATION: We report the case of a 29-year-old man who presented with lifelong sparse, fine scalp hair, bilateral malar erythema, soft fingernails, and dental anomalies (malocclusion with multiple caries). Routine laboratory tests were unremarkable except for reduced vitamins B1, B2, B6, and B9 (November 2024). Whole-exome sequencing (approximately 20,000 genes) identified a variant of uncertain significance in ANAPC1 (NM_022662.4:c.4907T>C, p.Val1636Ala); no reportable variants were found in ACMG-recommended secondary findings genes. Combination therapy (trazodone 50 mg qn, tanshinone capsules 1 g qid, isotretinoin 20 mg qod, topical halcinonide 10 mL mixed with minoxidil 60 mL 1 mL bid, and multivitamins 2 tablets tid) was initiated in November 2024. After 6 months, follow-up trichoscopy (May 2025) showed increased hair density and shaft thickness. CONCLUSION: We describe a patient with a Rothmund-Thomson syndrome-like phenotype who carried a heterozygous ANAPC1 variant of uncertain significance (VUS) and showed trichoscopic improvement after combination therapy. This singular observation hints at a possible phenotypic expansion associated with ANAPC1 but cannot establish a new genotype-phenotype correlation. The clinical improvement underscores that symptomatic management can be beneficial in complex genodermatoses, even in the absence of a definitive molecular diagnosis. The pathogenicity of the ANAPC1 VUS remains unconfirmed, necessitating functional validation and segregation studies in future research.

RECQL4, a RecQ family helicase, is essential for DNA replication and genome stability. Mutations in RECQL4 cause severe human disorders yet we do not fully understand its functions, particularly regarding ATP-dependent helicase activity. To understand RECQL4's functions further, we performed a genome-wide forward genetic screen using a murine model harbouring patient-like RECQL4 mutations. We identify KLHDC3, a substrate-binding subunit of the Cullin-RING ligase E3 complex, loss as the most significant rescue allele. KLHDC3 loss restores proliferation and replication in RECQL4-deficient cells by stabilizing trace levels of a truncated RECQL4 fragment containing the N-terminal 480 amino acids, lacking the helicase and C-terminal regions. This RECQL4 fragment forms after Cre-mediated recombination of the Recql4fl allele and contains a neo-degron sequence specific for KLHDC3. Although this mechanism does not apply to human mutations, it demonstrates that minimal RECQL4 levels, without any ATPase domain/activity, are sufficient to support DNA replication. This demonstrates that RECQL4 is an essential and non-redundant regulator of DNA replication and cell viability and that this activity does not require its ATP-dependent helicase activity.

This case report presents two Ecuadorian patients with Rothmund-Thomson syndrome type 2 (RTS2), an autosomal recessive disorder, who share a RECQL4 variant previously identified in another Ecuadorian patient, supporting the recurrent presence of this variant in the Ecuador population. Additionally, in the Case 2 patient with a suspected compound heterozygosity, a second pathogenic variant was identified that had not been previously reported in Ecuador. These findings underscore the importance of molecular diagnosis for accurate classification of RTS2, informed risk assessment, and improved clinical care, particularly in underrepresented populations.