Dynamic CpG island methylation landscape in oocytes and preimplantation embryos.

Elucidating how and to what extent CpG islands (CGIs) are methylated in germ cells is essential to understand genomic imprinting and epigenetic reprogramming. Here we present, to our knowledge, the first integrated epigenomic analysis of mammalian oocytes, identifying over a thousand CGIs methylated in mature oocytes. We show that these CGIs depend on DNMT3A and DNMT3L but are not distinct at the sequence level, including in CpG periodicity.

Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy.

Background: Generalized arterial calcification of infancy has been reported to be frequently lethal, and the efficiency of any therapy, including bisphosphonates, is unknown. A phosphate-poor diet markedly increases survival of NPP1 null mice, a model of generalized arterial calcification of infancy.

Methods And Results: We performed a multicenter genetic study and retrospective observational analysis of 55 subjects affected by generalized arterial calcification of infancy to identify prognostic factors.

Insights from Keystone: advances in the understanding of epigenetic regulation of the genome.

A report on the Keystone Symposium on Epigenetics, Development and Human Disease, Breckenridge, Colorado, USA, 5-10 January, 2009.

Transcription is required for establishment of germline methylation marks at imprinted genes.

Genomic imprinting requires the differential marking by DNA methylation of genes in male and female gametes. In the female germline, acquisition of methylation imprint marks depends upon the de novo methyltransferase Dnmt3a and its cofactor Dnmt3L, but the reasons why specific sequences are targets for Dnmt3a and Dnmt3L are still poorly understood. Here, we investigate the role of transcription in establishing maternal germline methylation marks.

Analysis of human alternative first exons and copy number variation of the GJA12 gene in patients with Pelizaeus-Merzbacher-like disease.

Pelizaeus-Merzbacher-like disease (PMLD) is a heterogeneous disease with primary hypomyelination of the central nervous system. Only the minority of patients have mutations in the coding region of the GJA12 gene encoding gap junction protein alpha 12, a subunit of intercellular channels highly expressed by oligodendrocytes, the myelin forming cells of the central nervous system. No other gene has been found so far to be mutated in PMLD besides GJA12.

Sequence-based bioinformatic prediction and QUASEP identify genomic imprinting of the KCNK9 potassium channel gene in mouse and human.

Genomic imprinting is the epigenetic marking of gene subsets resulting in monoallelic or predominant expression of one of the two parental alleles according to their parental origin. We describe the systematic experimental verification of a prioritized 16 candidate imprinted gene set predicted by sequence-based bioinformatic analyses. We used Quantification of Allele-Specific Expression by Pyrosequencing (QUASEP) and discovered maternal-specific imprinted expression of the Kcnk9 gene as well as strain-dependent preferential expression of the Rarres1 gene in E11.

Oligodendroglial transcription factor (OLIG1 and OLIG2) mutations are not associated with Pelizaeus-Merzbacher-like leukodystrophy.

The human phenotype with primarily impaired myelination is represented by hypomyelinating leukodystrophies. The most frequent form is Pelizaeus-Merzbacher disease, which is due to alterations in the PLP1 gene encoding the major myelin protein. Another form, Pelizaeus-Merzbacher-like disease, is partly associated with mutations in the GJA12 gene encoding gap junction protein alpha 12, but seems to be heterogeneous.

Expression profiling of uniparental mouse embryos is inefficient in identifying novel imprinted genes.

Imprinted genes are expressed from only one allele in a parent-of-origin-specific manner. We here describe a systematic approach to identify novel imprinted genes using quantification of allele-specific expression by Pyrosequencing, a highly accurate method to detect allele-specific expression differences. Sixty-eight candidate imprinted transcripts mapping to known imprinted chromosomal regions were selected from a recent expression profiling study of uniparental mouse embryos and analyzed.

Generalized arterial calcification of infancy: two siblings with prolonged survival.

In generalized arterial calcification of infancy (OMIM no. 208000), calcification of the media and proliferation of the intima lead to arterial stenoses. Most affected patients present with untreatable arterial hypertension and die within the first months of life.

Association of ENPP1 gene polymorphisms with hand osteoarthritis in a Chuvasha population.

Periarticular calcification is a common attendant symptom of generalized arterial calcification of infancy, a rare Mendelian disorder caused by mutations of the gene coding for ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). This prompted us to perform a family-based association study to test the hypothesis that genetic variation at the ENPP1 locus is involved in the etiology of osteoarthritis of the hand. The study population comprised 126 nuclear families with 574 adult individuals living in small villages in the Chuvasha and Bashkirostan autonomies of the Russian Federation.

Generalized arterial calcification of infancy: different clinical courses in two affected siblings.

Generalized arterial calcification of infancy (GACI) is a rare autosomal recessive disease caused by mutations in ENPP1. Due to extensive calcification of the arterial media associated with intimal proliferation leading to vascular occlusion, most affected children die within the first 6 months of life. We report on two Taiwanese siblings with an identical genotype, but different clinical course.

Association of ANKH gene polymorphisms with radiographic hand bone size and geometry in a Chuvasha population.

We performed a family-based association study to test the hypothesis that genetic variation at the human orthologue of the mouse progressive ankylosis gene (ANKH) is involved in determining bone size (BS) and bone geometry (BG). The study population comprised 126 nuclear families with 574 adult Chuvashian individuals living in small villages in the Russian Federation. Quantitative bone traits were determined by analyzing plain hand radiographs.

The mutational spectrum of ENPP1 as arising after the analysis of 23 unrelated patients with generalized arterial calcification of infancy (GACI).

Generalized arterial calcification of infancy (GACI), is characterized by calcification of the internal elastic lamina of large and medium-sized arteries and stenosis due to myointimal proliferation. Although survival to adulthood has been reported, most patients die within the first six months of life. Recently, we found mutations of ENPP1 coding for ecto-nucleotide pyrophosphatase/phosphodiesterase 1 to be associated with GACI in 8 of 11 families.

Functional consequences of a novel uromodulin mutation in a family with familial juvenile hyperuricaemic nephropathy.

Background: Familial juvenile hyperuricaemic nephropathy (FJHN) is an autosomal-dominant disorder featuring hyperuricaemia, low fractional urate excretion, interstitial nephritis and chronic renal failure. The responsible gene UMOD was recently identified. UMOD encodes for uromodulin or Tamm-Horsfall glycoprotein, the most abundant protein in normal urine.

Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.

The hypomyelinating leukodystrophies X-linked Pelizaeus-Merzbacher disease (PMD) and Pelizaeus-Merzbacher-like disease (PMLD) are characterized by nystagmus, progressive spasticity, and ataxia. In a consanguineous family with PMLD, we performed a genomewide linkage scan using the GeneChip Mapping EA 10K Array (Affymetrix) and detected a single gene locus on chromosome 1q41-q42. This region harbors the GJA12 gene, which encodes gap junction protein alpha 12 (or connexin 46.

Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification.

Idiopathic infantile arterial calcification (IIAC; OMIM 208000) is characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. We analyzed affected individuals from 11 unrelated kindreds and found that IIAC was associated with mutations that inactivated ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). This cell surface enzyme generates inorganic pyrophosphate (PP(i)), a solute that regulates cell differentiation and serves as an essential physiologic inhibitor of calcification.