The Genetics of 3-M Syndrome: Unravelling a Potential New Regulatory Growth Pathway

Hanson, Daniel; Murray, Phillip; Black, Graeme C M; Clayton, Peter E.

doi:10.1159/000334392

Cited by 36 publications

(32 citation statements)

References 108 publications

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“…Recently, Pnma14/CCDC8 was suggested to be one of the genes responsible for 3-M syndrome (Hanson et al, 2011a,b). 3-M syndrome is an autosomal-recessive disease characterized by severe postnatal growth restriction, leading to a significantly diminished stature.…”

Section: Pnma-family Genes From the Gypsy12_dr-related Ltr Retrotransmentioning

confidence: 99%

The role of genes domesticated from LTR retrotransposons and retroviruses in mammals

Kaneko-Ishino¹,

Ishino²

2012

Front. Microbio.

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The acquisition of multiple genes from long terminal repeat (LTR) retrotransposons occurred in mammals. Genes belonging to a sushi-ichi-related retrotransposon homologs (SIRH) family emerged around the time of the establishment of two viviparous mammalian groups, marsupials and eutherians. These genes encode proteins that are homologous to a retrotransposon Gag capsid protein and sometimes also have a Pol-like region. We previously demonstrated that PEG10 (SIRH1) and PEG11/RTL1 (SIRH2) play essential but different roles in placental development. PEG10 is conserved in both the marsupials and the eutherians, while PEG11/RTL1 is a eutherian-specific gene, suggesting that these two domesticated genes were deeply involved in the evolution of mammals via the establishment of the viviparous reproduction system. In this review, we introduce the roles of PEG10 and PEG11/RTL1 in mammalian development and evolution, and summarize the other genes domesticated from LTR retrotransposons and endogenous retroviruses (ERVs) in mammals. We also point out the importance of DNA methylation in inactivating and neutralizing the integrated retrotransposons and ERVs in the process of domestication.

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Section: Pnma-family Genes From the Gypsy12_dr-related Ltr Retrotransmentioning

confidence: 99%

The role of genes domesticated from LTR retrotransposons and retroviruses in mammals

Kaneko-Ishino¹,

Ishino²

2012

Front. Microbio.

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“…Besides CUL7 , two additional genes, OBSL1 and CCDC8 , have been found to be mutated in 3M syndrome. These three genes are mutated in a mutually exclusive manner, with CUL7 being the most frequently mutated (~65%), followed by OBSL1 (~30%) and CCDC8 (~5%) (Hanson et al, 2011a; Huber et al, 2011). Most mutations in these three genes cause truncations or frameshifts, indicating a loss-of-function as the cause of the disease.…”

Section: Introductionmentioning

confidence: 99%

The 3M Complex Maintains Microtubule and Genome Integrity

Yan

et al. 2014

Molecular Cell

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SUMMARY CUL7, OBSL1, and CCDC8 genes are mutated in a mutually exclusive manner in 3M and other growth retardation syndromes. The mechanism underlying the function of the three 3M genes in development is not known. We found that OBSL1 and CCDC8 form a complex with CUL7 and regulate the level and centrosomal localization of CUL7, respectively. CUL7 depletion results in altered microtubule dynamics, prometaphase arrest, tetraploidy and mitotic cell death. These defects are recaptured in CUL7 mutated 3M cells and can be rescued by wild-type, but not 3M patients-derived CUL7 mutants. Depletion of either OBSL1 or CCDC8 results in similar defects and sensitizes cells to microtubule damage as loss of CUL7 function. Microtubule damage reduces the level of CCDC8 that is required for the centrosomal localization of CUL7. We propose that CUL7, OBSL1, and CCDC8 proteins form a 3M complex that functions in maintaining microtubule and genome integrity and normal development.

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“…Currently, little is known about the specific functions of OBSL1 ; yet, it was suggested that the OBSL1 protein functions as a cytoskeletal adaptor protein linking the nuclear proteins to the cytoplasmic support network. Additionally, OBSL1 was also found to be expressed in a wide variety of cell types, suggestive of its role as a scaffolding protein (9). In addition, alterations in IGFBP-2 and IGFB5 messenger ribonucleic acid levels were previously documented to be associated with OBSL1 mutations in cases with 3M syndrome diagnoses (7).…”

Section: Discussionmentioning

confidence: 99%

A Rare Cause of Short Stature: 3M Syndrome in a Patient with Novel Mutation in OBSL1 Gene

Keskin

Şahin²,

Kurnaz³

et al. 2017

Jcrpe

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The Miller-McKusick-Malvaux (3M) syndrome is a rare autosomal disorder that can lead to short stature, dysmorphic features, and skeletal abnormalities with normal intelligence. A 16-month-old female patient had been referred to our clinic due to short stature. Case history revealed a birth weight of 1740 grams on the 39th week of gestation, with a birth length of 42 cm and no prior hereditary conditions of clinical significance in her family. On physical examination, her length was 67 cm [-3.6 standard deviation (SD) score], weight 7.2 kg (-2.9 SD score), and head circumference 42 cm (below 3rd percentile). She also had numerous characteristic physical features such as a triangular face, fleshy nose tip, a long philtrum, prominent mouth and lips, pointed chin, lumbar lordosis, and prominent heels. As her growth retardation had a prenatal onset and the physical examination results were suggestive of a characteristic profile, the diagnosis of 3M syndrome was strongly considered. Genetic assessment of the patient revealed a novel homozygous p.T45Nfs*40 mutation in the OBSL1 gene. It is recommended that physicians pay further attention to this condition in the differential diagnosis of children with severe short stature.

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The Genetics of 3-M Syndrome: Unravelling a Potential New Regulatory Growth Pathway

Cited by 36 publications

References 108 publications

The role of genes domesticated from LTR retrotransposons and retroviruses in mammals

The role of genes domesticated from LTR retrotransposons and retroviruses in mammals

The 3M Complex Maintains Microtubule and Genome Integrity

A Rare Cause of Short Stature: 3M Syndrome in a Patient with Novel Mutation in OBSL1 Gene

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