17 A De novo Recessive Mutation Causative of Mandibulofacial Dysostosis in Hereford Cattle

2021 ◽  
Vol 99 (Supplement_1) ◽  
pp. 27-27
Author(s):  
Renae L Sieck ◽  
Anna M Fuller ◽  
Patrick Bedwell ◽  
Jack Ward ◽  
Stacy Sanders ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Missense Mutation ◽  
De Novo ◽  
Pedigree Analysis ◽  
De Novo Mutation ◽  
Recessive Mutation ◽  
Hereford Cattle ◽  
Specific Regulation ◽  
Mandibulofacial Dysostosis ◽  
Mode Of Inheritance

Abstract In spring 2020, six Hereford calves presented with congenital craniofacial abnormalities attributed to a condition we termed mandibulofacial dysostosis (MD). Pedigree analysis revealed a single common ancestor shared by the sire and dam of each affected calf. We hypothesized that MD in Hereford cattle is attributed to a de novo mutation with an autosomal recessive mode of inheritance. To avoid production of affected calves, the objective of this study was to identify the cause of MD. Whole-genome sequencing (WGS) of 20 animals (3 affected, 7 obligate carriers, 10 related) yielded 143 variants matching the hypothesized mode of inheritance. Genotyping of 2 additional affected calves, 760 Herefords, and evaluation of WGS data from over 2,500 other individuals led to the discovery of a missense mutation (Chr26 g. 14404993 T >C) in CYP26C1 associated with MD. The amino acid change due to the CYP26C1 variant (p. L188P) is located in an α helix of the protein; modeling suggests the substitution breaks the helix. The mutation is predicted to be deleterious (SIFT = 0) and is otherwise conserved across species. In our data, all heterozygotes had at least one pedigree tie to the suspect founder. CYP26C1 plays a vital role in tissue-specific regulation of retinoic acid (RA) during embryonic development. Dysregulation of RA can result in teratogenesis by altering the endothelin-1 signaling pathway affecting the expression of Dlx genes, critical to mandibulofacial development. Further, multiple human conditions with similar pathologic characteristics are attributed to dysfunction of this gene and/or retinoic acid signaling. We conclude that this recessive missense mutation in CYP26C1 impacts the catalytic activity of the encoded enzyme, leading to excess RA and resulting in the MD phenotype. Breeders can now genotype their animals to identify carriers. These data also contribute to expanding the understanding of craniofacial development across species.

scholarly journals Mandibulofacial Dysostosis Attributed to a Recessive Mutation of CYP26C1 in Hereford Cattle

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1246
Author(s):  
Renae L. Sieck ◽  
Anna M. Fuller ◽  
Patrick S. Bedwell ◽  
Jack A. Ward ◽  
Stacy K. Sanders ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Pedigree Analysis ◽  
Vital Role ◽  
Recessive Mutation ◽  
Hereford Cattle ◽  
Dlx Genes ◽  
Specific Regulation ◽  
Α Helix ◽  
Lower Mandible ◽  
Mandibulofacial Dysostosis

In spring 2020, six Hereford calves presented with congenital facial deformities attributed to a condition we termed mandibulofacial dysostosis (MD). Affected calves shared hallmark features of a variably shortened and/or asymmetric lower mandible and bilateral skin tags present 2–10 cm caudal to the commissure of the lips. Pedigree analysis revealed a single common ancestor shared by the sire and dam of each affected calf. Whole-genome sequencing (WGS) of 20 animals led to the discovery of a variant (Chr26 g. 14404993T>C) in Exon 3 of CYP26C1 associated with MD. This missense mutation (p.L188P), is located in an α helix of the protein, which the identified amino acid substitution is predicted to break. The implication of this mutation was further validated through genotyping 2 additional affected calves, 760 other Herefords, and by evaluation of available WGS data from over 2500 other individuals. Only the affected individuals were homozygous for the variant and all heterozygotes had at least one pedigree tie to the suspect founder. CYP26C1 plays a vital role in tissue-specific regulation of retinoic acid (RA) during embryonic development. Dysregulation of RA can result in teratogenesis by altering the endothelin-1 signaling pathway affecting the expression of Dlx genes, critical to mandibulofacial development. We postulate that this recessive missense mutation in CYP26C1 impacts the catalytic activity of the encoded enzyme, leading to excess RA resulting in the observed MD phenotype.

Identification of a De Novo UNC13D L1000P Mutation in a Familial Hemophagocytic Lymphohistiocytosis Patient

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4927-4927
Author(s):  
Hongxing Liu ◽  
Fang Wang ◽  
Juan Zhu ◽  
Hui Wang ◽  
Ping Wu ◽  
...  
Keyword(s):  
Hair Follicle ◽  
Oral Mucosa ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Autosomal Recessive ◽  
De Novo ◽  
Autosomal Recessive Disorder ◽  
Pedigree Analysis ◽  
De Novo Mutation ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Gamete Formation

Abstract Abstract 4927 Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive disorder characterized by massive infiltration of several organs by activated lymphocytes and macrophages. Four causative genes have been identified for this autosomal recessive disorder (PRF1, UNC13D, STX11 and STXBP2). Till now, gene mutations carried by FHL cases reported in literature were all identified to be inherited when pedigree analysis was performed. But the mutation types of these genes were diversified, when and how these different kinds of mutations occurred is yet to know. Here we report the first de novo UNC13D L1000P mutation identified in a FHL patient. The patient was a 6 years old boy with fever (39-40.2°C), pancytopenia and hepatosplenomegaly. Blood test showed hemoglobin of 6.0g/dL, platelet count of 48×109/L, and white blood cell count of 0.96×109/L. ALT 91U/L, AST 68 IU/L, LDH 419IU/L, TP 67g/L, ALB 36g/L, Fibrinogen 2.03g/L, Serum ferrites 704ug/L. Ultrasound examination showed hepatosplenomegaly. Bone marrow morphological examination showed hemophagocytic phenomenon. Immunophenotyping of peripheral blood showed 68% of lymphocytes, no abnormal clonal cells were identified, the proportion of NK cells and perforin protein expression is normal. Herpes virus (HHV) type 1 to 8 screening showed EBV and HHV7 positive. Gene mutation screening for PRF1, UNC13D, STX11, STXBP2, SH2D1A and XIAP showed two UNC13D heterozygous mutations of c.1845_1847dupTGA/p.D615dup and c.2999T>C/p.L1000P, both mutations had never been reported in literature. The patient was diagnosed as FHL3 and got a remission by plasma exchange, antivirus, etoposide and dexamethasone treatment. And then he was performed allogeneic hematopoietic stem cell transplantation and soon got a complete implantation. When pedigree analysis was performed, only the D615dup mutation was inherited from his mother, the L1000P mutation was not seen in either his parents. The genetic relationship between the patient and his parents was confirmed by 15 STR polymorphism analysis using AB Identifilier Kit, and then the hereditary relationship of UNC13D gene was further confirmed by analysis of common polymorphism site within the UNC13D gene. Further pedigree analysis confirmed that the D615dup was inherited from the maternal lineage, but none of his paternal lineage member (including his father and grandparents) carrying L1000P mutation. The oral mucosa, nail, hair follicle and semen samples from the patient's father were all identified to be negative for L1000P mutation, but the oral mucosa, nail and hair follicle samples from the patient were all identified to be carrying the heterozygous L1000P mutation. The cDNA fragment including both D615dup and L1000P mutations from the patient was amplified by PCR and clone sequenced. By cloning and sequencing, we identified that the two mutations were separately located on different UNC13D alleles. Through comprehensive analysis of the results showed above, we deemed that the UNC13D L1000P mutation carrying by the patient is a de novo mutation, it most likely occurred during the process of male gamete formation from his father. It is known that there will be accidental event of de novo mutations during the process of gamete formation, and they are material basis of evolution and genetic disease. Due to the rarity of the incident, de novo mutation is hard to be observed in common Mendelian diseases and only have been reported in some very rare disease such as Proteus Syndrome. We are now reported the first observation of a de novo mutation in FHL patient, and we believe that the de novo UNC13D L1000P mutation and the hereditary UNC13D D615dup mutation each lead to defect of one UNC13D allele, and thus contribute to the genetic pathogenesis of the patient. We also believe this is evidence that the de novo mutation of UNC13D gene is a randomly and constantly accidental event in the general crowd. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A Chinese Patient with Spastic Paraplegia Type 4 with a De Novo Mutation in the SPAST Gene

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Li Xu ◽  
Zijuan Peng ◽  
Chunhui Zhou ◽  
Jiqing Wang ◽  
Hunjin Luo ◽  
...  
Keyword(s):  
Missense Mutation ◽  
De Novo ◽  
Chinese Patient ◽  
Chinese Woman ◽  
De Novo Mutation ◽  
Spastic Paraplegia ◽  
Gene Segregation ◽  
Whole Exome ◽  
The Family ◽  
Family Gene

Background. Spastic paraplegia type 4 (SPG4) is the most common type of hereditary spastic paraplegia (HSP) caused by mutations in the SPAST gene. Case Presentation. We report the case of a 27-year-old pregnant Chinese woman with HSP in whom we identified a missense mutation in the SPAST gene (c.1496G>A, p.Arg499His) and a nonsense mutation in the NEFH gene (c.289G>T, p.Glu97 ∗ ) via whole-exome sequencing; this finding corroborated that of Sanger sequencing. The patient exhibited the pure SPG4 phenotype with onset during childhood. The SPAST mutation was absent in the parents and paternal relatives. However, the NEFH mutation was identified in five people with no clinical phenotype. Based on theoretical conjecture and the family gene segregation information, we concluded that the SPAST mutation, but not the NEFH mutation, accounted for the proband’s phenotype. Eventually, the woman gave birth to a healthy baby girl with the NEFH mutation. Conclusion. In this report, we identified a missense mutation in the SPAST gene (p.Arg499His) in a 27-year-old pregnant Chinese woman with HSP. We believe that this study expands the knowledge about the clinical parameters and mutation spectrum of SPG4.

De novo mutation of PHEX in a type 1 diabetes patient

2016 ◽  
Vol 29 (5) ◽  
Author(s):  
Chen Fang ◽  
Hui Li ◽  
Xiaozhen Li ◽  
Wenjin Xiao ◽  
Yun Huang ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Missense Mutation ◽  
X Chromosome ◽  
De Novo ◽  
Diabetes Patient ◽  
De Novo Mutation

AbstractA new missense mutation on the X chromosome (

scholarly journals Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kohei Kitagawa ◽  
Kensuke Matsumura ◽  
Masayuki Baba ◽  
Momoka Kondo ◽  
Tomoya Takemoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Mouse Models ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutation ◽  
Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

scholarly journals The L1-dependant and Pol III transcribed Alu retrotransposon, from its discovery to innate immunity

2021 ◽  
Vol 48 (3) ◽  
pp. 2775-2789
Author(s):  
Ludwig Stenz
Keyword(s):  
Human Genome ◽  
Viral Infections ◽  
De Novo ◽  
Current Knowledge ◽  
Innate Immune ◽  
De Novo Mutation ◽  
Neuronal Diversity ◽  
Alu Sequences ◽  
Pol Iii ◽  
The Brain

AbstractThe 300 bp dimeric repeats digestible by AluI were discovered in 1979. Since then, Alu were involved in the most fundamental epigenetic mechanisms, namely reprogramming, pluripotency, imprinting and mosaicism. These Alu encode a family of retrotransposons transcribed by the RNA Pol III machinery, notably when the cytosines that constitute their sequences are de-methylated. Then, Alu hijack the functions of ORF2 encoded by another transposons named L1 during reverse transcription and integration into new sites. That mechanism functions as a complex genetic parasite able to copy-paste Alu sequences. Doing that, Alu have modified even the size of the human genome, as well as of other primate genomes, during 65 million years of co-evolution. Actually, one germline retro-transposition still occurs each 20 births. Thus, Alu continue to modify our human genome nowadays and were implicated in de novo mutation causing diseases including deletions, duplications and rearrangements. Most recently, retrotransposons were found to trigger neuronal diversity by inducing mosaicism in the brain. Finally, boosted during viral infections, Alu clearly interact with the innate immune system. The purpose of that review is to give a condensed overview of all these major findings that concern the fascinating physiology of Alu from their discovery up to the current knowledge.

scholarly journals Publisher Correction: Germline de novo mutation clusters arise during oocyte aging in genomic regions with high double-strand-break incidence

2021 ◽  
Author(s):  
Jakob M. Goldmann ◽  
Vladimir B. Seplyarskiy ◽  
Wendy S. W. Wong ◽  
Thierry Vilboux ◽  
Pieter B. Neerincx ◽  
...  
Keyword(s):  
De Novo ◽  
Strand Break ◽  
Double Strand Break ◽  
De Novo Mutation ◽  
Oocyte Aging ◽  
Genomic Regions

Sleep Exacerbations and Facial Twitching: Diagnostic Clues for ADCY5-Related Dyskinesias

2020 ◽  
Author(s):  
Margherita Nosadini ◽  
Gianluca D'Onofrio ◽  
Maria Federica Pelizza ◽  
Concetta Luisi ◽  
Davide Padrin ◽  
...  
Keyword(s):  
Movement Disorder ◽  
Developmental Delay ◽  
De Novo ◽  
Brain Magnetic Resonance Imaging ◽  
Neurological Impairment ◽  
De Novo Mutation ◽  
Oligoclonal Bands ◽  
Emotional Stimuli ◽  
Childhood Onset ◽  
Ataxic Gait

Abstract Background Mutations in the adenylate cyclase 5 (ADCY5) gene are associated with childhood-onset paroxysmal dyskinesia. Methods We report a new video-documented case of pediatric ADCY5-related dyskinesia with de novo ADCY5 mutation. Results A boy born to nonconsanguineous parents after an uneventful pregnancy had developmental delay and hypotonia. At the age of 7 months, he presented with paroxysmal jerky–choreic–dystonic involuntary movements in wakefulness involving limbs, trunk, and face, exacerbated by emotional stimuli. These episodes gradually worsened in duration and frequency: at the age of 2.5 years, they occurred up to six times per day, and appeared also during sleep in prolonged bouts; the boy also had basal choreoathetoid–dystonic movements, hyperactivity, paraparetic–ataxic gait, generalized hypotonia with brisk tendon reflexes, drooling, and language delay with intellectual disability. Brain magnetic resonance imaging, electroencephalogram, electromyogram, eye review, metabolic investigations, oligoclonal bands, and autoantibodies were normal. Extensive genetic testing had not let to a diagnosis, until a heterozygous de novo mutation c.1252C > T (p.Arg418Trp) was identified in the ADCY5 gene. Clonazepam had partial effectiveness. The boy walked at the age of 3.5 years. At the age of 5 years, the paroxysmal movement disorder has slightly improved. Conclusion ADCY5 mutations should be considered among the differential diagnoses of early-onset paroxysmal choreic–athetosic–myoclonic–dystonic movement disorder involving limbs, trunk, and face, in patients with global neurological impairment with hypotonia and developmental delay. Facial dyskinesias and exacerbation by drowsiness/sleep and emotional stimuli are important clues that may allow a timely recognition of the disorder and avoidance of unnecessary diagnostic investigations.

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