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The Journal of Dermatology Feb 2021
Topics: Humans; Japan; Mutation; Pedigree; Piebaldism; Proto-Oncogene Proteins c-kit
PubMed: 33155701
DOI: 10.1111/1346-8138.15684 -
Veterinary and Animal Science Jun 2020Most canine deafness is linked to white pigmentation caused by the piebald locus, shown to be the gene (), but studies have failed to identify a deafness cause. The...
Most canine deafness is linked to white pigmentation caused by the piebald locus, shown to be the gene (), but studies have failed to identify a deafness cause. The coding regions of have not been shown to be mutated in deaf dogs, leading us to pursue genes acting on or controlled by . We have genotyped DNA from 502 deaf and hearing Australian cattle dogs, Dalmatians, and English setters, breeds with a high deafness prevalence. Genome-wide significance was not attained in any of our analyses, but we did identify several suggestive associations. Genome-wide association studies (GWAS) in complex hereditary disorders frequently fail to identify causative gene variants, so advanced bioinformatics data mining techniques are needed to extract information to guide future studies. STRING diagrams are graphical representations of known and predicted networks of protein-protein interactions, identifying documented relationships between gene proteins based on the scientific literature, to identify functional gene groupings to pursue for further scrutiny. The STRING program predicts associations at a preset confidence level and suggests biological functions based on the identified genes. Starting with (1) genes within 500 kb of GWAS-suggested SNPs, (2) known pigmentation genes, (3) known human deafness genes, and (4) genes identified from proteomic analysis of the cochlea, we generated STRING diagrams that included these genes. We then reduced the number of genes by excluding genes with no relationship to auditory function, pigmentation, or relevant structures, and identified clusters of genes that warrant further investigation.
PubMed: 32734119
DOI: 10.1016/j.vas.2020.100118 -
Evaluating possible maternal effect lethality and genetic background effects in Naa10 knockout mice.PloS One 2024Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10,...
Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/y male mice on the inbred genetic background in this different animal facility.
Topics: Animals; N-Terminal Acetyltransferase A; N-Terminal Acetyltransferase E; Mice; Female; Mice, Knockout; Male; Phenotype; Genetic Background; Maternal Inheritance; Mice, Inbred C57BL
PubMed: 38713657
DOI: 10.1371/journal.pone.0301328 -
Communications Biology Feb 2020Two coat-color mutations, , which changes coat color from wild-type agouti to black, and , which induces irregular white spotting, are the characteristics of Japanese...
Two coat-color mutations, , which changes coat color from wild-type agouti to black, and , which induces irregular white spotting, are the characteristics of Japanese fancy mouse strain JF1/Ms. In our article, we reported that insertion of a rare type of endogenous retrovirus β4 has caused both coat color mutations. Although there are some reports on the roles of β4 in the mouse genome, further studies on β4 will uncover new features of endogenous retrovirus sequences.
Topics: Alleles; Animals; Biological Evolution; Endogenous Retroviruses; Hair Color; Mice; Mutagenesis, Insertional; Quantitative Trait, Heritable
PubMed: 32020010
DOI: 10.1038/s42003-020-0781-z -
Genes Sep 2021A 1-month-old, female, smooth-haired miniature Dachshund with dilute color and neurological defects was investigated. The aim of this study was to characterize the...
A 1-month-old, female, smooth-haired miniature Dachshund with dilute color and neurological defects was investigated. The aim of this study was to characterize the clinical signs, histopathological changes and underlying genetic defect. The puppy had visible coat color dilution and was unable to hold its head on its own or to remain in a stable prone position for an extended period. Histopathological examination revealed an accumulation of clumped melanin and deposition of accumulated keratin within the hair follicles, accompanied by dermal pigmentary incontinence. These dermatological changes were compatible with the histopathology described in dogs with an -related dilute coat color. We sequenced the genome of the affected dog and compared the data to 795 control genomes. , coding for myosin VA, was investigated as the top functional candidate gene. This search revealed a private homozygous frameshift variant in , XM_022412522.1:c.4973_4974insA, predicted to truncate 269 amino acids (13.8%) of the wild type myosin VA protein, XP_022268230.1:p.(Asn1658Lysfs*28). The genotypes of the index family showed the expected co-segregation with the phenotype and the mutant allele was absent from 142 additionally genotyped, unrelated Dachshund dogs. loss of function variants cause Griscelli type 1 syndrome in humans, lavender foal in horses and the phenotype of the mouse mutant. Based on the available data, together with current knowledge on other species, we propose the identified frameshift insertion as a candidate causative variant for the observed dermatological and neurological signs in the investigated dog.
Topics: Alleles; Animals; Dog Diseases; Dogs; Frameshift Mutation; Genetic Predisposition to Disease; Genotype; Hair Color; Hearing Loss, Sensorineural; Homozygote; Humans; Myosin Heavy Chains; Myosin Type V; Phenotype; Piebaldism; Pigmentation; Pigmentation Disorders
PubMed: 34680875
DOI: 10.3390/genes12101479 -
American Journal of Medical Genetics.... Nov 2020Griscelli syndrome type 2 (GS2) is a rare autosomal recessive disorder caused by pathogenic variants in the RAB27A gene and characterized by partial albinism,...
Griscelli syndrome type 2 (GS2) is a rare autosomal recessive disorder caused by pathogenic variants in the RAB27A gene and characterized by partial albinism, immunodeficiency, and occasional hematological and neurological involvement. We reviewed and analyzed the medical records of 12 individuals with GS2 from six families belonging to a highly consanguineous Qatari tribe and with a recurrent pathogenic variant in the RAB27A gene (NM_004580.4: c.244C > T, p.Arg82Cys). Detailed demographic, clinical, and molecular data were collected. Cutaneous manifestations were the most common presentation (42%), followed by neurological abnormalities (33%) and immunodeficiency (25%). The most severe manifestation was HLH (33%). Among the 12 patients, three patients (25%) underwent HSCT, and four (33%) died. The cause of death in all four patients was deemed HLH, providing evidence for this complication's fatal nature. Interestingly, two affected patients (16%) were asymptomatic. This report highlights the broad spectrum of clinical presentations of GS2 associated with a founder variant in the RAB27A gene (c.244C > T, p.Arg82Cys). Early suspicion of GS2 among Qatari patients with cutaneous manifestations, neurological findings, immunodeficiency, and HLH would shorten the diagnostic odyssey, guide early and appropriate treatment, and prevent fatal outcomes.
Topics: Adolescent; Child; Child, Preschool; Exome; Family Health; Female; Founder Effect; Homozygote; Humans; Infant; Lymphohistiocytosis, Hemophagocytic; Male; Pedigree; Phenotype; Piebaldism; Primary Immunodeficiency Diseases; Qatar; Recurrence; Young Adult; rab27 GTP-Binding Proteins
PubMed: 32856792
DOI: 10.1002/ajmg.a.61829 -
Clinical, Cosmetic and Investigational... 2024Piebaldism is a rare genetic disorder caused by mutations and clinically characterized by fixed depigmented patches throughout the body. Herein, a case of piebaldism in...
Piebaldism is a rare genetic disorder caused by mutations and clinically characterized by fixed depigmented patches throughout the body. Herein, a case of piebaldism in which the depigmented patches regressed as the patient grew older, along with the development of multiple café-au-lait macules, is described. The likely pathogenic, heterozygous c.1991-2A>G variant was detected as the potential cause of this unusual piebaldism phenotype. This case provides new knowledge on genotype-phenotype correlation of mutations for piebaldism etiology and presentation.
PubMed: 38524391
DOI: 10.2147/CCID.S449691 -
Skin Appendage Disorders Feb 2021Piebaldism is a rare autosomal dominant disorder characterized by leucoderma with leucotrichia. We describe a case of white forelock repigmentation in an infant with...
Piebaldism is a rare autosomal dominant disorder characterized by leucoderma with leucotrichia. We describe a case of white forelock repigmentation in an infant with piebaldism, thanks to a photograph sent by the patient's mother to our dermatology clinic, during COVID-19 pandemic.
PubMed: 33791342
DOI: 10.1159/000512033 -
BioRxiv : the Preprint Server For... Jan 2024Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, , encodes...
Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, , encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in . In mice, is not an essential gene, as there exists a paralogous gene, , that substantially rescues knockout mice from embryonic lethality, whereas double knockouts ( Naa12 are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous female mice, but we do observe a small amount of embryonic lethality in the male mice on the inbred genetic background in this different animal facility.
PubMed: 37163119
DOI: 10.1101/2023.04.27.538618 -
Pediatric Dermatology Jan 2021Griscelli syndrome type 2 is a rare autosomal recessive disorder characterized by hypopigmentation, silvery hair, and immunological dysfunction with no primary...
Griscelli syndrome type 2 is a rare autosomal recessive disorder characterized by hypopigmentation, silvery hair, and immunological dysfunction with no primary neurological impairment. We report an 18-month-old girl with Griscelli syndrome type 2 who presented to the dermatology department for cutaneous granulomas that developed following live-attenuated vaccination. Two compound heterozygous variants in the RAB27A gene were subsequently identified. She developed hemophagocytic lymphohistiocytosis, the key immunological concern, at age 5 years.
Topics: Child, Preschool; Female; Granuloma; Humans; Immunologic Deficiency Syndromes; Infant; Lymphohistiocytosis, Hemophagocytic; Piebaldism; Primary Immunodeficiency Diseases
PubMed: 32965739
DOI: 10.1111/pde.14370