Two cases of maternal uniparental disomy 14 with a phenotype overlapping with the Prader-Willi phenotype

Berends, Maran J.W.; Hordijk, Roel; Scheffer, Hans; Oosterwijk, Jan C.; Halley, Dicky; Sorgedrager, Niels

doi:10.1002/(sici)1096-8628(19990507)84:1<76::aid-ajmg16>3.0.co;2-f

Cited by 68 publications

(65 citation statements)

References 9 publications

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“…Examination of the adipose tissue suggests that both enhanced adipocyte differentiation and enhanced fat cell maturation contribute to the increase in adipose mass seen in Pref-1-null mice. Obesity is often observed in mUPD14 (1,16). Increased adipose mass in Pref-1-null mice, therefore, parallels the human mUPD14 obesity phenotype.…”

Section: Discussionmentioning

confidence: 91%

“…However, it is also possible that the nontranslated transcripts may act as RNA effector molecules to regulate gene expression in a manner similar to the Air (for antisense igf2r RNA) transcript described for the igf2r gene (15). The overlapping phenotypes of Pref-1-null mice and human mUPD14 indicate that the obesity, skeletal malformation, blepharophimosis, and growth retardation in human mUPD14 (1,5,8,16) can be attributed to Pref-1. On the other hand, hypotonic and early-puberty phenotypes observed in mUPD14 are not apparent in Pref-1-null mice and may therefore be caused by misexpression of another imprinted gene, possibly peg11.…”

Section: Discussionmentioning

confidence: 99%

“…A cluster of imprinted genes has recently been discovered on mouse chromosome 12 and in VOL. 22,2002 TARGETED DISRUPTION OF THE pref-1 GENE 5589 a syntenic region of human chromosome 14 (1,5,6,8). At this locus, the pref-1, peg11, and dat genes are paternally expressed, while the gtl2, antipeg11, and meg8 genes are maternally expressed (3).…”

Section: Discussionmentioning

confidence: 99%

“…Studies of mouse mUPD12 and human mUPD14 have suggested that imprinted genes present in this chromosomal region are important for embryo survival and growth, with affected individuals having deformities that include scoliosis, hypotonicity, early puberty, obesity, and blepharophimosis (1,5,6,16,29,32). However, the imprinted gene or genes responsible and their relevant phenotypes have not been determined.…”

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confidence: 99%

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Mice Lacking Paternally Expressed Pref-1/Dlk1 Display Growth Retardation and Accelerated Adiposity

Moon

Smas

Lee

et al. 2002

Molecular and Cellular Biology

411

362

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Preadipocyte factor 1 (Pref-1/Dlk1) inhibits in vitro adipocyte differentiation and has been recently reported to be a paternally expressed imprinted gene at human chromosome 14q32. Studies on human chromosome 14 deletions and maternal uniparental disomy (mUPD) 14 suggest that misexpression of a yet-to-be-identified imprinted gene or genes present on chromosome 14 causes congenital disorders. We generated Pref-1 knockout mice to assess the role of Pref-1 in growth and in vivo adipogenesis and to determine the contribution of Pref-1 in mUPD. Pref-1-null mice display growth retardation, obesity, blepharophimosis, skeletal malformation, and increased serum lipid metabolites. Furthermore, the phenotypes observed in Pref-1-null mice are present in heterozygotes that harbor a paternally inherited, but not in those with a maternally inherited pref-1-null allele. Our results demonstrate that Pref-1 is indeed paternally expressed and is important for normal development and for homeostasis of adipose tissue mass. We also suggest that Pref-1 is responsible for most of the symptoms observed in mouse mUPD12 and human mUPD14. Pref-1-null mice may be a model for obesity and other pathologies of human mUPD14.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Mice Lacking Paternally Expressed Pref-1/Dlk1 Display Growth Retardation and Accelerated Adiposity

Moon

Smas

Lee

et al. 2002

Molecular and Cellular Biology

411

362

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“…This is illustrated by the presence of high prenatal mortality, growth retardation, obesity, skeletal malformations, and abnormalities of hematopoiesis in mice deficient in Dlk1 (7,8). Also, in the human syndrome of maternal uniparental disomy 14 (where Dlk1 is silent), patients exhibit obesity, hypotonia, premature puberty, macrocephaly, short stature, and small hands (9). Dlk1 has been known for several years as a negative regulator of adipocyte differentiation (10).…”

mentioning

confidence: 99%

dlk1/FA1 Regulates the Function of Human Bone Marrow Mesenchymal Stem Cells by Modulating Gene Expression of Pro-inflammatory Cytokines and Immune Response-related Factors

Abdallah

Boissy

Tan

et al. 2007

Journal of Biological Chemistry

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dlk1/FA1 (delta-like 1/fetal antigen-1) is a member of the epidermal growth factor-like homeotic protein family whose expression is known to modulate the differentiation signals of mesenchymal and hematopoietic stem cells in bone marrow. We have demonstrated previously that Dlk1 can maintain the human bone marrow mesenchymal stem cells (hMSC) in an undifferentiated state. To identify the molecular mechanisms underlying these effects, we compared the basal gene expression pattern in Dlk1-overexpressing hMSC cells (hMSC-dlk1) versus control hMSC (negative for Dlk1 expression) by using Affymetrix HG-U133A microarrays. In response to Dlk1 expression, 128 genes were significantly up-regulated (with >2-fold; p < 0.001), and 24% of these genes were annotated as immune response-related factors, including pro-inflammatory cytokines, in addition to factors involved in the complement system, apoptosis, and cell adhesion. Also, addition of purified FA1 to hMSC up-regulated the same factors in a dose-dependent manner. As biological consequences of up-regulating these immune response-related factors, we showed that the inhibitory effects of dlk1 on osteoblast and adipocyte differentiation of hMSC are associated with Dlk1-induced cytokine expression. Furthermore, Dlk1 promoted B cell proliferation, synergized the immune response effects of the bacterial endotoxin lipopolysaccharide on hMSC, and led to marked transactivation of the NF-B. Our data suggest a new role for Dlk1 in regulating the multiple biological functions of hMSC by influencing the composition of their microenvironment "niche." Our findings also demonstrate a role for Dlk1 in mediating the immune response.

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Unusual phenotype in partial trisomy 14

Lemire

Cardwell

1999

Am. J. Med. Genet.

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An 8-year-old boy with partial trisomy 14q and phenotype distinct from previously reported cases is described. The mother carries a balanced 9;14 reciprocal translocation. The patient presented with minor facial anomalies, developmental delay, hyperphagia, and obesity. Imprinting of maternal chromosome 14 or disruption of one or more genes on chromosome 9 may be responsible for our patient's manifestations.

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Two cases of maternal uniparental disomy 14 with a phenotype overlapping with the Prader-Willi phenotype

Cited by 68 publications

References 9 publications

Mice Lacking Paternally Expressed Pref-1/Dlk1 Display Growth Retardation and Accelerated Adiposity

Mice Lacking Paternally Expressed Pref-1/Dlk1 Display Growth Retardation and Accelerated Adiposity

dlk1/FA1 Regulates the Function of Human Bone Marrow Mesenchymal Stem Cells by Modulating Gene Expression of Pro-inflammatory Cytokines and Immune Response-related Factors

Unusual phenotype in partial trisomy 14

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