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Genes Nov 2022Albinism is a genetic disorder, present worldwide, caused by mutations in genes affecting melanin production or transport in the skin, hair and eyes. To date, mutations...
Albinism is a genetic disorder, present worldwide, caused by mutations in genes affecting melanin production or transport in the skin, hair and eyes. To date, mutations in at least 20 different genes have been identified. Oculo-cutaneous Albinism type IV (OCA4) is the most frequent form in Asia but has been reported in all populations, including Europeans. Little is known about the genotype-phenotype correlation. We identified two main phenotypes via the analysis of 30 OCA4 patients with a molecularly proven diagnosis. The first, found in 20 patients, is clinically indistinguishable from the classical OCA1 phenotype. The genotype-to-phenotype correlation suggests that this phenotype is associated with homozygous or compound heterozygous nonsense or deletion variants with frameshift leading to translation interruption in the gene. The second phenotype, found in 10 patients, is characterized by very mild hypopigmentation of the hair (light brown or even dark hair) and skin that is similar to the general population. In this group, visual acuity is variable, but it can be subnormal, foveal hypoplasia can be low grade or even normal, and nystagmus may be lacking. These mild to moderate phenotypes are associated with at least one missense mutation in .
Topics: Humans; Piebaldism; Mutation; Mutation, Missense; Phenotype; Genotype
PubMed: 36553465
DOI: 10.3390/genes13122198 -
Journal of Visualized Experiments : JoVE Mar 2022Melanocytes are specialized neural crest-derived cells present in the epidermal skin. These cells synthesize melanin pigment that protects the genome from harmful...
Melanocytes are specialized neural crest-derived cells present in the epidermal skin. These cells synthesize melanin pigment that protects the genome from harmful ultraviolet radiations. Perturbations in melanocyte functioning lead to pigmentary disorders such as piebaldism, albinism, vitiligo, melasma, and melanoma. Zebrafish is an excellent model system to understand melanocyte functions. The presence of conspicuous pigmented melanocytes, ease of genetic manipulation, and availability of transgenic fluorescent lines facilitate the study of pigmentation. This study employs the use of wild-type and transgenic zebrafish lines that drive green fluorescent protein (GFP) expression under mitfa and tyrp1 promoters that mark various stages of melanocytes. Morpholino-based silencing of candidate genes is achieved to evaluate the phenotypic outcome on larval pigmentation and is applicable to screen for regulators of pigmentation. This protocol demonstrates the method from microinjection to imaging and fluorescence-activated cell sorting (FACS)-based dissection of phenotypes using two candidate genes, carbonic anhydrase 14 (Ca14) and a histone variant (H2afv), to comprehensively assess the pigmentation outcome. Further, this protocol demonstrates segregating candidate genes into melanocyte specifiers and differentiators that selectively alter melanocyte numbers and melanin content per cell, respectively.
Topics: Animals; Melanocytes; Pigmentation; Pigmentation Disorders; Reverse Genetics; Zebrafish
PubMed: 35312674
DOI: 10.3791/62955 -
QJM : Monthly Journal of the... Feb 2020
Topics: Child, Preschool; Fatal Outcome; Female; Hair; Humans; Hypopigmentation; Lymphohistiocytosis, Hemophagocytic; Piebaldism; Primary Immunodeficiency Diseases
PubMed: 31199490
DOI: 10.1093/qjmed/hcz144 -
Journal of Fish Biology Jan 2023Hypomelanosis refers to a suite of skin pigment abnormalities, including albinism, leucism and piebaldism. While documented across many vertebrate species, examples of...
Hypomelanosis refers to a suite of skin pigment abnormalities, including albinism, leucism and piebaldism. While documented across many vertebrate species, examples of hypomelanosis are rarely seen in chondrichthyans, with little insight into the potential effects on survival. Here, we report the first observation of abnormal skin pigmentation indicative of piebaldism in the Atlantic nurse shark Ginglymostoma cirratum, representing only the second reported case of skin aberrations for this species. This extremely rare observation is discussed in the broader context of fitness variation and long-term survival.
Topics: Animals; Piebaldism; Sharks
PubMed: 36196931
DOI: 10.1111/jfb.15238 -
Annals of Dermatology Oct 2019We present 9-year-old fraternal twins from a family with piebaldism, having congenital depigmented macules and meeting the diagnostic criteria for neurofibromatosis type...
We present 9-year-old fraternal twins from a family with piebaldism, having congenital depigmented macules and meeting the diagnostic criteria for neurofibromatosis type 1 () due to the multiple café-au-lait macules (CALMs) and intertriginous freckling at the same time. It's still a debatable issue that CALMs and intertriginous freckling may be seen in the clinical spectrum of piebaldism or these patients should be regarded as coexistence of piebaldism and . However, based on recent literature and our patients' findings, we suggest that this rare phenotypic variant of piebaldism may not need the careful clinical follow-up and molecular testing for . Besides, it may be suitable that these individuals with piebaldism showing -like clinical phenotypes should be further tested for and gene mutations.
PubMed: 33911651
DOI: 10.5021/ad.2019.31.5.567 -
Molecular Genetics and Genomics : MGG Mar 2023Griscelli syndrome type 1 (GS1) is a rare inherited autosomal recessive disease caused by a deleterious variant in the MYO5A gene and characterized by general... (Review)
Review
Griscelli syndrome type 1 (GS1) is a rare inherited autosomal recessive disease caused by a deleterious variant in the MYO5A gene and characterized by general hypopigmentation, neurological symptoms, motor disability, hypotonia, and vision abnormality. Only nine pathogenic variants in the MYO5A gene have been confirmed in association with the GS1. All of the reported pathogenic variants are truncating. Herein, two siblings from a consanguineous Iranian family with abnormal pigmentation and neurological symptoms were referred for genetic counseling. Whole-exome sequencing (WES) revealed a novel homozygous truncating variant c.1633_1634delAA (p.Asn545Glnfs*10) in the MYO5A gene, which was completely co-segregated with the phenotype in all affected and unaffected family members. Computational analysis and protein modeling demonstrated the deleterious effects of this variant on the structure and function of the protein. The variant, according to ACMG guidelines, was classified as pathogenic. Besides the novelty of the identified variant, our patients manifested more severe clinical symptoms and presented distal hyperlaxity in all four limbs, which was a new finding. In conclusion, we expanded the mutational and phenotypic spectrum of the GS1. Moreover, by studying clinical manifestations in all molecularly confirmed reported cases, provided a comprehensive overview of clinical presentation, and attempted to find a genotype-phenotype correlation.
Topics: Humans; Iran; Disabled Persons; Motor Disorders; Piebaldism; Mutation; Pedigree
PubMed: 36651988
DOI: 10.1007/s00438-022-01971-6 -
Frontiers in Cell and Developmental... 2024Reptilian species, particularly snakes and lizards, are emerging models of animal coloration. Here, I focus on the role of the TFEC transcription factor in snake and...
Reptilian species, particularly snakes and lizards, are emerging models of animal coloration. Here, I focus on the role of the TFEC transcription factor in snake and lizard coloration based on a study on wild-type and piebald ball pythons. Genomic mapping previously identified a TFEC mutation linked to the piebald ball python phenotype. The association of TFEC with skin coloration was further supported by gene-editing experiments in the brown anole lizard. However, novel histological analyses presented here reveal discrepancies between the ball python and the anole TFEC mutants phenotype, cautioning against broad generalizations. Indeed, both wild-type and piebald ball pythons completely lack iridophores, whereas the TFEC anole lizard mutants lose their iridophores compared to the wild-type anole. Based on these findings, I discuss the potential role of the MiT/TFE family in skin pigmentation across vertebrate lineages and advocate the need for developmental analyses and additional gene-editing experiments to explore the reptilian coloration diversity.
PubMed: 38385026
DOI: 10.3389/fcell.2024.1358828 -
Journal of Pediatric Hematology/oncology Aug 2020Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled and excessive immune responses with high mortality. We aimed to define mortality-related...
Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled and excessive immune responses with high mortality. We aimed to define mortality-related parameters in HLH secondary to primary immunodeficiency (PID). A total of 28 patients with HLH between the years 2013 and 2017 were enrolled in the study. The patients were evaluated in 2 groups including PID with hypopigmentation (n=7) (Chédiak-Higashi syndrome [CHS] and Griscelli syndrome type 2 [GS2]) and other PIDs (n=21). The median age of the study population was 23 (4.3 to 117.0) months at the time of the diagnosis of HLH. Central nervous system involvement was recorded in 7 (GS2/CHS patients [n=4], other PIDs [n=3], P=0.026), and death was observed in 9 patients (GS2/CHS patients [n=1], other PIDs [n=8], P=0.371). Five patients (3 GS2/CHS and 2 other PID patients) underwent hematopoietic stem cell transplantation. Low serum albumin level was the only variable associated with the mortality and albumin levels less than the cut-off value of 3.07 g/dL increased mortality 5.8 times in patients with HLH secondary to PID. We presented a single-center experience consisting of patients with HLH secondary to PID with a mortality rate of 32.1%. Hypoalbuminemia was the only risk factor to increase the overall mortality rate of HLH.
Topics: Chediak-Higashi Syndrome; Child; Child, Preschool; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lymphohistiocytosis, Hemophagocytic; Male; Piebaldism; Primary Immunodeficiency Diseases; Prognosis; Risk Factors; Survival Rate
PubMed: 32324696
DOI: 10.1097/MPH.0000000000001803 -
ELife Aug 2021Amino-terminal acetylation is catalyzed by a set of N-terminal acetyltransferases (NATs). The NatA complex (including X-linked Naa10 and Naa15) is the major...
Amino-terminal acetylation is catalyzed by a set of N-terminal acetyltransferases (NATs). The NatA complex (including X-linked Naa10 and Naa15) is the major acetyltransferase, with 40-50% of all mammalian proteins being potential substrates. However, the overall role of amino-terminal acetylation on a whole-organism level is poorly understood, particularly in mammals. Male mice lacking show no globally apparent in vivo amino-terminal acetylation impairment and do not exhibit complete embryonic lethality. Rather nulls display increased neonatal lethality, and the majority of surviving undersized mutants exhibit a combination of hydrocephaly, cardiac defects, homeotic anterior transformation, piebaldism, and urogenital anomalies. is a previously unannotated -like paralog with NAT activity that genetically compensates for . Mice deficient for have no apparent phenotype, whereas mice deficient for and display embryonic lethality. The discovery of adds to the currently known machinery involved in amino-terminal acetylation in mice.
Topics: Acetylation; Animals; Female; Male; Mice; Mice, Knockout; N-Terminal Acetyltransferase A; N-Terminal Acetyltransferase E
PubMed: 34355692
DOI: 10.7554/eLife.65952 -
American Journal of Translational... 2020Piebaldism is a rare autosomal dominant disorder characterized by congenital patchy depigmentation of the scalp, forehead, trunk, and limbs. The gene is the mainly...
INTRODUCTION
Piebaldism is a rare autosomal dominant disorder characterized by congenital patchy depigmentation of the scalp, forehead, trunk, and limbs. The gene is the mainly causative gene to this disease. But how is involved in piebaldism remains unclear.
METHODS
Whole exome sequencing was used to explore the genetic cause of a familial case of piebaldism. Sanger sequencing was used to validate the variant. To further examine the variant's pathogenicity, the wild type and the mutated plasmids were constructed and transfected into HEK293T cells. Next STAT5 expression, a signaling target of KIT, was detected by western blotting to explore the potential molecular mechanism of the variant in piebaldism. Based on the classification of the given variant, prenatal diagnosis was further performed in this family.
RESULTS
A novel pathogenic variant of c.2326G>A (NM_000222.2) was identified in this family. The phosphorylation of STAT5 was reduced in the mutant transfected cells compared to the wild type after stem cell factor (SCF) treatment, indicating that the KIT signaling was dysfunctional and supported that the variant was a pathogenic one. Prenatal diagnosis results indicated that the fetus exhibited the same genotype as the proband.
CONCLUSION
We identified a novel pathogenic variant in the patient with piebaldism to expand the variation spectrum of . The functional study indicated that the mutant KIT was dysfunctional in KIT signaling. The pathogenic variant identification enriches the knowledge about the genotype/phenotype correlation and could serve as the basis for genetic counseling and prenatal diagnosis.
PubMed: 33194047
DOI: No ID Found