Biallelic and <i>De Novo</i> Variants in <i>DONSON</i> Reveal a Clinical Spectrum of Cell Cycle‐opathies with Microcephaly, Dwarfism and Skeletal Abnormalities

Karaca, Ender; Posey, Jennifer E.; Bostwick, Bret L.; Liu, Pengfei; Gezdirici, Alper; Yeşil, Gözde; Akdemir, Zeynep Coban; Bayram, Yavuz; Harms, Frederike L.; Meinecke, Peter; Alawi, Malik; Bacino, Carlos A.; Sutton, V. Reid; Kortüm, Fanny; Lupski, James R.

doi:10.1002/ajmg.a.61315

Cited by 15 publications

(20 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although a wealth of data shows that DONSON mutations lead to PM, skeletal abnormalities, and probably hematopoiesis defects [14,[16][17][18][19][20][21], consequences of DONSON loss of function have not been assessed in animal models. Here, we identify Donson expression in the major proliferation zones of the mouse telencephalon.…”

Section: Discussionmentioning

confidence: 99%

“…The developmental defects were attributed to decreased checkpoint activity and chromosomal instability due to impaired DONSON function. Subsequent studies linked DONSON mutations to micromelia syndrome, Meier-Gorlin syndrome, Seckel-like syndrome, Femoral Facial syndrome, and microcephaly, short stature and limb abnormalities, which are all characterized by microcephaly as well as skeletal and craniofacial abnormalities [16][17][18][19][20][21]. The wealth of clinical data indicating that DONSON mutations can lead to severe developmental defects are opposed by the lack of studies assessing…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The microcephaly gene Donson is essential for progenitors of cortical glutamatergic and GABAergic neurons

et al. 2021

View full text Add to dashboard Cite

Biallelic mutations in DONSON, an essential gene encoding for a replication fork protection factor, were linked to skeletal abnormalities and microcephaly. To better understand DONSON function in corticogenesis, we characterized Donson expression and consequences of conditional Donson deletion in the mouse telencephalon. Donson was widely expressed in the proliferation and differentiation zones of the embryonic dorsal and ventral telencephalon, which was followed by a postnatal expression decrease. Emx1-Cre-mediated Donson deletion in progenitors of cortical glutamatergic neurons caused extensive apoptosis in the early dorsomedial neuroepithelium, thus preventing formation of the neocortex and hippocampus. At the place of the missing lateral neocortex, these mutants exhibited a dorsal extension of an early-generated paleocortex. Targeting cortical neurons at the intermediate progenitor stage using Tbr2-Cre evoked no apparent malformations, whereas Nkx2.1-Cre-mediated Donson deletion in subpallial progenitors ablated 75% of Nkx2.1-derived cortical GABAergic neurons. Thus, the early telencephalic neuroepithelium depends critically on Donson function. Our findings help explain why the neocortex is most severely affected in individuals with DONSON mutations and suggest that DONSON-dependent microcephaly might be associated with so far unrecognized defects in cortical GABAergic neurons. Targeting Donson using an appropriate recombinase is proposed as a feasible strategy to ablate proliferating and nascent cells in experimental research.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The microcephaly gene Donson is essential for progenitors of cortical glutamatergic and GABAergic neurons

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Thus, it remains an open question as to whether a direct link exists between MGS and aberrant cilia formation. Following the original studies identifying mutations in ORC , CDC6 and CDT1 as causing MGS, additional reports revealed MCM5, CDC45 , GMNN and DONSON variants in MGS patients ( Figure 4 and Figure 5 ) [ 5 , 69 , 70 , 71 , 76 , 77 , 78 ]. One patient was identified with a compound heterozygous mutation in MCM5 resulting in a reduction in MCM5 and MCM2 on chromatin, consistent with an inability to stably load MCM2-7 onto chromatin ( Figure 4 and Supplementary Table S1 ) [ 70 ].…”

Section: Diseasesmentioning

confidence: 99%

“…It remains unclear whether mutations in DONSON represent true MGS or represent a related syndrome [ 5 , 77 , 153 ]. Patients with DONSON mutations present with primordial dwarfism, but not all have the classic triad of MGS symptoms [ 5 , 76 , 78 ]. Molecular studies of DONSON demonstrated a function in DNA replication fork stabilization rather than DNA replication initiation [ 5 ].…”

Section: Diseasesmentioning

confidence: 99%

Congenital Diseases of DNA Replication: Clinical Phenotypes and Molecular Mechanisms

Schmit

Bielinsky

2021

IJMS

View full text Add to dashboard Cite

Deoxyribonucleic acid (DNA) replication can be divided into three major steps: initiation, elongation and termination. Each time a human cell divides, these steps must be reiteratively carried out. Disruption of DNA replication can lead to genomic instability, with the accumulation of point mutations or larger chromosomal anomalies such as rearrangements. While cancer is the most common class of disease associated with genomic instability, several congenital diseases with dysfunctional DNA replication give rise to similar DNA alterations. In this review, we discuss all congenital diseases that arise from pathogenic variants in essential replication genes across the spectrum of aberrant replisome assembly, origin activation and DNA synthesis. For each of these conditions, we describe their clinical phenotypes as well as molecular studies aimed at determining the functional mechanisms of disease, including the assessment of genomic stability. By comparing and contrasting these diseases, we hope to illuminate how the disruption of DNA replication at distinct steps affects human health in a surprisingly cell-type-specific manner.

show abstract

“…Additional proteins, as part of the pre‐initiation complex (preIC), bind to the preRC at the onset of S phase, to unwind the DNA and allow access for the DNA polymerases, commencing DNA replication (Fragkos, Ganier, Coulombe, & Mechali, 2015). All the proteins encoded by MGORS‐associated genes serve essential roles in licensing of genomic origins as part of the pre‐replication complex (ORC1, ORC4, ORC6, CDT1, CDC6, MCM5), as a negative regulator of DNA replication (GMNN), or a component of the replication pre‐initiation complex (CDC45) or the replisome (DONSON) (Bicknell, Bongers, et al, 2011; Bicknell, Walker, et al, 2011; Burrage et al, 2015; Fenwick et al, 2016; Guernsey et al, 2011; Karaca et al, 2019; Knapp et al, 2020; Vetro et al, 2017). CDT1 acts to assist the loading of the two heterohexameric MCM helicase complexes onto the ORC complex, and associates with the ORC complex in a transient manner (Ticau, Friedman, Ivica, Gelles, & Bell, 2015).…”

Section: Introductionmentioning

confidence: 99%

Successful pregnancies in an adult with Meier‐Gorlin syndrome harboring biallelic CDT1 variants

Knapp

Murray

Temple

et al. 2020

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Meier‐Gorlin syndrome is an autosomal recessively inherited disorder of growth retardation, accompanied by microtia and patellae a/hypoplasia and characteristic facies. Pathogenic variants in genes associated with the initiation of DNA replication underlie the condition, with biallelic variants in CDT1 the most common cause. Using 10× Chromium genome sequencing, we report CDT1 variants in an adult female, with an inframe amino acid deletion inherited in trans with a deep intronic variant which likely serves as the branchpoint site in Intron 8. Splicing defects arising from this variant were confirmed through in vitro analysis. At 49 years, she represents the oldest patient with a molecular diagnosis described in the literature and is the first reported patient with Meier‐Gorlin syndrome to have carried a successful pregnancy to term. Both of her pregnancies were complicated by postpartum hemorrhage and upon subsequent necessary hysterectomy, revealed uterine abnormalities. There is scant knowledge on reproductive ability and success in patients with Meier‐Gorlin syndrome. Successful pregnancies among other clinically recognizable forms of primordial dwarfism have also not been described previously. This case is therefore of clinical interest for many forms of inherited growth retardation, and will assist in providing more information and clinical guidance for females of reproductive age.

show abstract

Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle‐opathies with Microcephaly, Dwarfism and Skeletal Abnormalities

Abstract: Co-occurrence of primordial dwarfism and microcephaly together with particular skeletal findings are seen in a wide range of Mendelian syndromes including

Cited by 15 publications

References 38 publications

The microcephaly gene Donson is essential for progenitors of cortical glutamatergic and GABAergic neurons

The microcephaly gene Donson is essential for progenitors of cortical glutamatergic and GABAergic neurons

Congenital Diseases of DNA Replication: Clinical Phenotypes and Molecular Mechanisms

Successful pregnancies in an adult with Meier‐Gorlin syndrome harboring biallelic CDT1 variants

Contact Info

Product

Resources

About