Mechanisms and pathways of growth failure in primordial dwarfism.

By Anna Klingseisen, A. P. Jackson. 2011

231 citations recorded by the source corpus.

The greatest difference between species is size; however, the developmental mechanisms determining organism growth remain poorly understood. Primordial dwarfism is a group of human single-gene disorders with extreme global growth failure (which includes Seckel syndrome, microcephalic osteodysplastic primordial dwarfism I [MOPD] types I and II, and Meier-Gorlin syndrome). Ten genes have now been identified for microcephalic primordial dwarfism, encoding proteins involved in fundamental cellular processes including genome replication (ORC1 [origin recognition complex 1], ORC4, ORC6, CDT1, and CDC6), DNA damage response (ATR [ataxia-telangiectasia and Rad3-related]), mRNA splicing (U4atac), and centrosome function (CEP152, PCNT, and CPAP). Here, we review the cellular and developmental mechanisms underlying the pathogenesis of these conditions and address whether further study of these genes could provide novel insight into the physiological regulation of organism growth.

Subfields: Molecular Biology, Rheumatology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Johannes C. Walter
2. Masato T. Kanemaki
3. Sachiko Muramatsu

Citations in the corpus

• In silico protein interaction screening uncovers DONSON’s role in replication initiation (2023, background): “This would reduce total cell number, resulting in the hypo-cellularitythatunderliesmicrocephalicdwarfism ( 21 ).”
• Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle-opathies with Microcephaly, Dwarfism and Skeletal Abnormalities (2019, background): “These findings are consistent with the molecular pathogenesis proposed to underlie MPDs: perturbed genome replication and cell proliferation (Klingseisen & Jackson, 2011).”
• Meier-Gorlin syndrome (2015, unknown): “This would result in a reduction of the total cell number and thereby diminish overall growth [24, 25].”
• The expanding genetic and clinical landscape associated with Meier-Gorlin syndrome (2023, background): “Associated genes encode proteins involved in processes required for timely cell cycle progression such as cell cycle checkpoint, centrosome duplication and coordination, DNA replication, and DNA repair [1].”
• PRIM1 deficiency causes a distinctive primordial dwarfism syndrome (2020, unknown): “Microcephalic primordial dwarfism (MPD) disorders constitute several Mendelian syndromes characterized by intrauterine growth retardation, short stature, and microcephaly (Klingseisen and Jackson 2011).”
• Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome (2017, background): “…disease While progress has been made in understanding the mechanisms of RNA splicing and how splicing patterns relate to DNA sequence (Barash et al. 2010; Xiong et al. 2015), much of the genomic code mediating splicing remains unknown (Lewandowska 2013; Guigo and Valcarcel 2015; Lee and Rio 2015).”
• DONSON facilitates Cdc45 and GINS chromatin association and is essential for DNA replication initiation (2023, background): “Howe v er, the human and Xenopus TopBP1 homologues are much larger proteins, containing eight BRCT domains (1-8), with an additional N-terminal BRCT domain identified in human TopBP1, named BRCT0 ( 51 ).”