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Animal Genetics Oct 2022Hereditary ataxias are common among canine breeds with various molecular etiology. We identified a hereditary ataxia in young-adult Australian Shepherd dogs...
Hereditary ataxias are common among canine breeds with various molecular etiology. We identified a hereditary ataxia in young-adult Australian Shepherd dogs characterized by uncoordinated movements and spasticity, worsening progressively and leading to inability to walk. Pedigree analysis suggested an autosomal recessive transmission. By whole genome sequencing and variant filtering of an affected dog we identified a PNPLA8:c.1169_1170dupTT variant. This variant, located in PNPLA8 (Patatin Like Phospholipase Domain Containing 8), was predicted to induce a PNPLA8:p.(His391PhefsTer394) frameshift, leading to a premature stop codon in the protein. The truncated protein was predicted to lack the functional patatin catalytic domain of PNPLA8, a calcium-independent phospholipase. PNPLA8 is known to be essential for maintaining mitochondrial energy production through tailoring mitochondrial membrane lipid metabolism and composition. The Australian Shepherd ataxia shares molecular and clinical features with Weaver syndrome in cattle and the mitochondrial-related neurodegeneration associated with PNPLA8 loss-of-function variants in humans. By genotyping a cohort of 85 control Australian Shepherd dogs sampled in France, we found a 4.7% carrier frequency. The PNPLA8:c.[1169_1170dupTT] allele is easily detectable with a genetic test to avoid at-risk matings.
Topics: Animals; Australia; Cattle; Cattle Diseases; Dog Diseases; Dogs; Frameshift Mutation; Humans; Pedigree; Phospholipases; Spinocerebellar Degenerations
PubMed: 35864734
DOI: 10.1111/age.13245 -
Cold Spring Harbor Molecular Case... Aug 2018Overgrowth syndromes are a clinically heterogeneous group of disorders characterized by localized or generalized tissue overgrowth and varying degrees of developmental...
Co-occurrence of a maternally inherited duplication and a paternally inherited pathogenic variant in in a child with growth retardation and severe short stature: atypical Weaver syndrome or evidence of a dosage effect?
Overgrowth syndromes are a clinically heterogeneous group of disorders characterized by localized or generalized tissue overgrowth and varying degrees of developmental and intellectual disability. An expanding list of genes associated with overgrowth syndromes include the histone methyltransferase genes and , which cause Weaver and Sotos syndrome, respectively, and the DNA methyltransferase () gene that results in Tatton-Brown-Rahman syndrome (TBRS). Here, we describe a 5-year-old female with a paternally inherited pathogenic mutation in (c.2050C>T, p.Arg684Cys) and a maternally inherited 505-kb duplication of uncertain significance at 2p23.3 (encompassing five genes, including ) who presented with intrauterine growth restriction, slow postnatal growth, short stature, hypotonia, developmental delay, and neuroblastoma diagnosed at the age of 8 mo. Her father had tall stature, dysmorphic facial features, and intellectual disability consistent with Weaver syndrome, whereas her mother had short stature, cognitive delays, and chronic nonprogressive leukocytosis. It has been previously shown that EZH2 directly controls DNA methylation through physical association with DNMTs, including DNMT3A, with concomitant H3K27 methylation and CpG promoter methylation leading to repression of EZH2 target genes. Interestingly, NSD1 is involved in H3K36 methylation, a mark associated with transcriptional activation, and exhibits exquisite dosage sensitivity leading to overgrowth when deleted and severe undergrowth when duplicated in vivo. Although there is currently no evidence of dosage effects for , the co-occurrence of a duplication involving this gene and a pathogenic alteration in in a patient with severe undergrowth is suggestive of a similar paradigm and further study is warranted.
Topics: Abnormalities, Multiple; Adult; Child; Congenital Hypothyroidism; Craniofacial Abnormalities; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; Enhancer of Zeste Homolog 2 Protein; Female; Gene Dosage; Gene Duplication; Hand Deformities, Congenital; Humans; Male; Pedigree; Phenotype
PubMed: 29802153
DOI: 10.1101/mcs.a002899 -
Stem Cell Reports Sep 2022Mutations in the embryonic ectoderm development (EED) cause Weaver syndrome, but whether and how EED affects embryonic brain development remains elusive. Here, we...
Mutations in the embryonic ectoderm development (EED) cause Weaver syndrome, but whether and how EED affects embryonic brain development remains elusive. Here, we generated a mouse model in which Eed was deleted in the forebrain to investigate the role of EED. We found that deletion of Eed decreased the number of upper-layer neurons but not deeper-layer neurons starting at E16.5. Transcriptomic and genomic occupancy analyses revealed that the epigenetic states of a group of cortical neurogenesis-related genes were altered in Eed knockout forebrains, followed by a decrease of H3K27me3 and an increase of H3K27ac marks within the promoter regions. The switching of H3K27me3 to H3K27ac modification promoted the recruitment of RNA-Pol2, thereby enhancing its expression level. The small molecule activator SAG or Ptch1 knockout for activating Hedgehog signaling can partially rescue aberrant cortical neurogenesis. Taken together, we proposed a novel EED-Gli3-Gli1 regulatory axis that is critical for embryonic brain development.
Topics: Animals; Brain; Epigenesis, Genetic; Hedgehog Proteins; Histones; Mice; Nerve Tissue Proteins; Neurogenesis; Polycomb Repressive Complex 2; Zinc Finger Protein GLI1; Zinc Finger Protein Gli3
PubMed: 35931079
DOI: 10.1016/j.stemcr.2022.07.004 -
American Journal of Human Genetics Jan 2003Sotos syndrome is a childhood overgrowth syndrome characterized by a distinctive facial appearance, height and head circumference >97th percentile, advanced bone age,...
Sotos syndrome is a childhood overgrowth syndrome characterized by a distinctive facial appearance, height and head circumference >97th percentile, advanced bone age, and developmental delay. Weaver syndrome is characterized by the same criteria but has its own distinctive facial gestalt. Recently, a 2.2-Mb chromosome 5q35 microdeletion, encompassing NSD1, was reported as the major cause of Sotos syndrome, with intragenic NSD1 mutations identified in a minority of cases. We evaluated 75 patients with childhood overgrowth, for intragenic mutations and large deletions of NSD1. The series was phenotypically scored into four groups, prior to the molecular analyses: the phenotype in group 1 (n=37) was typical of Sotos syndrome; the phenotype in group 2 (n=13) was Sotos-like but with some atypical features; patients in group 3 (n=7) had Weaver syndrome, and patients in group 4 (n=18) had an overgrowth condition that was neither Sotos nor Weaver syndrome. We detected three deletions and 32 mutations (13 frameshift, 8 nonsense, 2 splice-site, and 9 missense) that are likely to impair NSD1 functions. The truncating mutations were spread throughout NSD1, but there was evidence of clustering of missense mutations in highly conserved functional domains between exons 13 and 23. There was a strong correlation between presence of an NSD1 alteration and clinical phenotype, in that 28 of 37 (76%) patients in group 1 had NSD1 mutations or deletions, whereas none of the patients in group 4 had abnormalities of NSD1. Three patients with Weaver syndrome had NSD1 mutations, all between amino acids 2142 and 2184. We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes.
Topics: Abnormalities, Multiple; Amino Acid Sequence; Carrier Proteins; Child; Chromosome Deletion; Chromosomes, Human, Pair 5; Craniofacial Abnormalities; DNA Mutational Analysis; Developmental Disabilities; Exons; Female; Growth Disorders; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Intracellular Signaling Peptides and Proteins; Introns; Male; Molecular Sequence Data; Mutation; Nuclear Proteins; Pedigree; Phenotype; Polymorphism, Genetic; Protein Structure, Tertiary; Sequence Deletion; Syndrome
PubMed: 12464997
DOI: 10.1086/345647 -
Clinical Epigenetics Jul 2018Investigating how epigenetic information is transmitted through the mammalian germline is the key to understanding how this information impacts on health and disease...
BACKGROUND
Investigating how epigenetic information is transmitted through the mammalian germline is the key to understanding how this information impacts on health and disease susceptibility in offspring. EED is essential for regulating the repressive histone modification, histone 3 lysine 27 tri-methylation (H3K27me3) at many developmental genes.
RESULTS
In this study, we used oocyte-specific Zp3-Cre recombinase (Zp3Cre) to delete Eed specifically in mouse growing oocytes, permitting the study of EED function in oocytes and the impact of depleting EED in oocytes on outcomes in offspring. As EED deletion occurred only in growing oocytes and females were mated to normal wild type males, this model allowed the study of oocyte programming without confounding factors such as altered in utero environment. Loss of EED from growing oocytes resulted in a significant overgrowth phenotype that persisted into adult life. Significantly, this involved increased adiposity (total fat) and bone mineral density in offspring. Similar overgrowth occurs in humans with Cohen-Gibson (OMIM 617561) and Weaver (OMIM 277590) syndromes, that result from de novo germline mutations in EED or its co-factor EZH2, respectively. Consistent with a role for EZH2 in human oocytes, we demonstrate that de novo germline mutations in EZH2 occurred in the maternal germline in some cases of Weaver syndrome. However, deletion of Ezh2 in mouse oocytes resulted in a distinct phenotype compared to that resulting from oocyte-specific deletion of Eed.
CONCLUSIONS
This study provides novel evidence that altering EED-dependent oocyte programming leads to compromised offspring growth and development in the next generation.
Topics: Adiposity; Animals; Bone Density; Disease Models, Animal; Enhancer of Zeste Homolog 2 Protein; Female; Gene Deletion; Growth Disorders; Humans; Male; Maternal Inheritance; Mice; Oocytes; Polycomb Repressive Complex 2
PubMed: 30005706
DOI: 10.1186/s13148-018-0526-8 -
American Journal of Medical Genetics.... May 2013NSD1 and EZH2 are SET domain-containing histone methyltransferases that play key roles in the regulation of transcription through histone modification and chromatin...
NSD1 and EZH2 are SET domain-containing histone methyltransferases that play key roles in the regulation of transcription through histone modification and chromatin modeling: NSD1 preferentially methylates lysine residue 36 of histone 3 (H3K36) and is primarily associated with active transcription, while EZH2 shows specificity for lysine residue 27 (H3K27) and is associated with transcriptional repression. Somatic dysregulation of NSD1 and EZH2 have been associated with tumorigenesis. NSD1, as a fusion transcript with NUP98, plays a key role in leukemogenesis, particularly childhood acute myeloid leukemia. EZH2 is a major proto-oncogene and mono- and biallelic activating and inactivating somatic mutations occur as early events in the development of tumors, particularly poor prognosis hematopoietic malignancies. Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap. NSD1 mutations that cause Sotos syndrome are loss-of-function, primarily truncating mutations or missense mutations at key residues in functional domains. EZH2 mutations that cause Weaver syndrome are primarily missense variants and the rare truncating mutations reported to date are in the last exon, suggesting that simple haploinsufficiency is unlikely to be generating the overgrowth phenotype although the exact mechanism has not yet been determined. Many additional questions about the molecular and clinical features of NSD1 and EZH2 remain unanswered. However, studies are underway to address these and, as more cases are ascertained and technology improves, it is hoped that these will, in time, be answered.
Topics: Enhancer of Zeste Homolog 2 Protein; Germ-Line Mutation; Growth; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Intracellular Signaling Peptides and Proteins; Nuclear Proteins; Polycomb Repressive Complex 2; Proto-Oncogene Mas; Proto-Oncogenes
PubMed: 23592277
DOI: 10.1002/ajmg.c.31359 -
American Journal of Human Genetics Jan 2012We used trio-based whole-exome sequencing to analyze two families affected by Weaver syndrome, including one of the original families reported in 1974. Filtering of rare...
We used trio-based whole-exome sequencing to analyze two families affected by Weaver syndrome, including one of the original families reported in 1974. Filtering of rare variants in the affected probands against the parental variants identified two different de novo mutations in the enhancer of zeste homolog 2 (EZH2). Sanger sequencing of EZH2 in a third classically-affected proband identified a third de novo mutation in this gene. These data show that mutations in EZH2 cause Weaver syndrome.
Topics: Abnormalities, Multiple; Adolescent; Adult; Base Sequence; Child; Child, Preschool; Congenital Hypothyroidism; Craniofacial Abnormalities; DNA Mutational Analysis; DNA-Binding Proteins; Enhancer of Zeste Homolog 2 Protein; Exome; Female; Hand Deformities, Congenital; Humans; Infant; Male; Molecular Sequence Data; Mutation; Pedigree; Polycomb Repressive Complex 2; Transcription Factors; Young Adult
PubMed: 22177091
DOI: 10.1016/j.ajhg.2011.11.018 -
Medicine Jan 2018Sugammadex is a cylodextrin derivate that encapsulates steroidal neuromuscular blocker agents and is reported as a safe and well-tolerated drug. In this case report, we... (Review)
Review
Clinically suspected anaphylaxis induced by sugammadex in a patient with Weaver syndrome undergoing restrictive mammoplasty surgery: A case report with the literature review.
RATIONALE
Sugammadex is a cylodextrin derivate that encapsulates steroidal neuromuscular blocker agents and is reported as a safe and well-tolerated drug. In this case report, we present a patient who developed grade 3 anaphylaxis just after sugammadex administration.
PATIENT CONCERNS
A 22-year-old woman with diagnosis of Weaver syndrome was scheduled for bilateral mammoplasty and resection of unilateral accessory breast tissue resection. Anesthesia was induced and maintained by propofol, rocuronium, and remifentanil. At the end of the operation, sugammadex was administered and resulted in initially hypotension and bradycardia then the situation worsened by premature ventricular contraction and bigeminy with tachycardia, bronchospasm, and hypoxia.
DIAGNOSIS
The Ring and Messmer clinical severity scale grade 3 anaphylactic reaction occurred just after sugammadex injection and the patient developed prolonged hypotension with recurrent cardiac arrhythmias in postoperative 12 hours.
INTERVENTIONS
Treatment was initiated bolus injections of ephedrine, epinephrine, lidocaine, steroids and antihistaminic and continued with lidocaine bolus dosages and norepinephrine infusion for the postoperative period.
OUTCOMES
The general condition of the patient improved to normal 3 hours after the sugammadex injection, and she was moved to the intensive care unit. At 2nd and 8th hours of intensive care unit follow-up, she developed premature ventricular contraction and bigeminy with the heart rate of 130 to 135 beats/min, which returned to sinus rhythm with 50 mg lidocaine. After that, no symptoms were observed and the patient was discharged to plastic surgery clinic at the following day.
LESSONS
Sugammadex may result in life-treating anaphylactic reaction even in a patient who did not previously expose to drug. Moreover, prolonged cardiovascular collapse and cardiac arrhythmias may occur.
Topics: Abnormalities, Multiple; Anaphylaxis; Congenital Hypothyroidism; Craniofacial Abnormalities; Female; Hand Deformities, Congenital; Humans; Mammaplasty; Sugammadex; Young Adult; gamma-Cyclodextrins
PubMed: 29505006
DOI: 10.1097/MD.0000000000009661 -
Indian Journal of Human Genetics May 2007We describe a girl with Sotos syndrome presenting at two and a half years age with developmental delay. She has camptodactyly which has not previously been reported in...
We describe a girl with Sotos syndrome presenting at two and a half years age with developmental delay. She has camptodactyly which has not previously been reported in Sotos syndrome but is a common finding in Weaver syndrome. Both these conditions have been reported to have NSD1 gene mutations. This report is consistent with the conditions being allelic.
PubMed: 21957350
DOI: 10.4103/0971-6866.34711 -
Frontiers in Cell and Developmental... 2020Usually overlooked by physicians, olfactory abnormalities are not uncommon. Olfactory malformations have recently been reported in an emerging group of genetic disorders...
Usually overlooked by physicians, olfactory abnormalities are not uncommon. Olfactory malformations have recently been reported in an emerging group of genetic disorders called Mendelian Disorders of the Epigenetic Machinery (MDEM). This study aims to determine the prevalence of olfactory malformations in a heterogeneous group of subjects with MDEM. We reviewed the clinical data of 35 patients, 20 females and 15 males, with a mean age of 9.52 years (SD 4.99). All patients had a MDEM and an already available high-resolution brain MRI scan. Two experienced neuroradiologists reviewed the MR images, noting abnormalities and classifying olfactory malformations. Main findings included Corpus Callosum, Cerebellar vermis, and olfactory defects. The latter were found in 11/35 cases (31.4%), of which 7/11 had Rubinstein-Taybi syndrome (RSTS), 2/11 had CHARGE syndrome, 1/11 had Kleefstra syndrome (KLFS), and 1/11 had Weaver syndrome (WVS). The irregularities mainly concerned the olfactory bulbs and were bilateral in 9/11 patients. With over 30% of our sample having an olfactory malformation, this study reveals a possible new diagnostic marker for MDEM and links the epigenetic machinery to the development of the olfactory bulbs.
PubMed: 32850830
DOI: 10.3389/fcell.2020.00710