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Gastroenterology Nov 2020Hirschsprung disease (HSCR) is a life-threatening birth defect in which the distal colon is devoid of enteric neural ganglia. HSCR is treated by surgical removal of...
BACKGROUND & AIMS
Hirschsprung disease (HSCR) is a life-threatening birth defect in which the distal colon is devoid of enteric neural ganglia. HSCR is treated by surgical removal of aganglionic bowel, but many children continue to have severe problems after surgery. We studied whether administration of glial cell derived neurotrophic factor (GDNF) induces enteric nervous system regeneration in mouse models of HSCR.
METHODS
We performed studies with four mouse models of HSCR: Holstein (Hol, a model for trisomy 21-associated HSCR), TashT (TashT, a model for male-biased HSCR), Piebald-lethal (Ednrb, a model for EDNRB mutation-associated HSCR), and Ret (with aganglionosis induced by mycophenolate). Mice were given rectal enemas containing GDNF or saline (control) from postnatal days 4 through 8. We measured survival times of mice, and colon tissues were analyzed by histology, immunofluorescence, and immunoblots. Neural ganglia regeneration and structure, bowel motility, epithelial permeability, muscle thickness, and neutrophil infiltration were studied in colon tissues and in mice. Stool samples were collected, and microbiomes were analyzed by 16S rRNA gene sequencing. Time-lapse imaging and genetic cell-lineage tracing were used to identify a source of GDNF-targeted neural progenitors. Human aganglionic colon explants from children with HSCR were cultured with GDNF and evaluated for neurogenesis.
RESULTS
GDNF significantly prolonged mean survival times of Hol mice, Ednrb mice, and male TashT mice, compared with control mice, but not Ret mice (which had mycophenolate toxicity). Mice given GDNF developed neurons and glia in distal bowel tissues that were aganglionic in control mice, had a significant increase in colon motility, and had significant decreases in epithelial permeability, muscle thickness, and neutrophil density. We observed dysbiosis in fecal samples from Hol mice compared with feces from wild-type mice; fecal microbiomes of mice given GDNF were similar to those of wild-type mice except for Bacteroides. Exogenous luminal GDNF penetrated aganglionic colon epithelium of Hol mice, inducing production of endogenous GDNF, and new enteric neurons and glia appeared to arise from Schwann cells within extrinsic nerves. GDNF application to cultured explants of human aganglionic bowel induced proliferation of Schwann cells and formation of new neurons.
CONCLUSIONS
GDNF prolonged survival, induced enteric neurogenesis, and improved colon structure and function in 3 mouse models of HSCR. Application of GDNF to cultured explants of aganglionic bowel from children with HSCR induced proliferation of Schwann cells and formation of new neurons. GDNF might be developed for treatment of HSCR.
Topics: Animals; Colon; Disease Models, Animal; Dysbiosis; Enteric Nervous System; Gastrointestinal Microbiome; Gastrointestinal Motility; Glial Cell Line-Derived Neurotrophic Factor; Hirschsprung Disease; Humans; Intestinal Absorption; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Nerve Regeneration; Neural Stem Cells; Neurogenesis; Permeability; Recovery of Function; Schwann Cells; Tissue Culture Techniques
PubMed: 32687927
DOI: 10.1053/j.gastro.2020.07.018 -
Scandinavian Journal of Immunology Jun 2021Griscelli syndrome (GS) is a rare autosomal recessive disease with characteristic pigment distribution, and there are currently 3 types according to the underlying... (Meta-Analysis)
Meta-Analysis Review
Griscelli syndrome (GS) is a rare autosomal recessive disease with characteristic pigment distribution, and there are currently 3 types according to the underlying genetic defect and clinical features. We present the case of a girl born from consanguineous parents who presented with predominant neurologic symptoms, silvery hair and granulomatous skin lesions. Cerebral magnetic resonance revealed diffuse white matter lesions, and central nervous system (CNS) lymphocytic infiltration was suspected. The patient underwent haematopoietic stem cell transplantation with graft failure and autologous reconstitution. She developed elevated liver enzyme with a cholestatic pattern. Multiple liver biopsies revealed centrilobular cholestasis and unspecific portal inflammation that improved with immunomodulatory treatment. She was revealed to have an impaired cytotoxicity in NK cells and a decreased expression of RAB27A. However, no variants were found in the gene. All types of GS present with pigment dilution and irregular pigment clumps that can be seen through light microscopy in hair and skin biopsy. Dermic granulomas and immunodeficiency with infectious and HLH predisposition have been described in GS type 2 (GS2). Neurologic alterations might be seen in GS type 1 (GS1) and GS type 2 (GS2), due to different mechanisms. GS1 presents with neurologic impairment secondary to myosin Va role in neuronal development and synapsis. Meanwhile, GS2 can present with neurologic impairment secondary to SNC HLH. Clinical features and cytotoxicity might aid in differentiating GS1 and GS2, especially since treatment differs.
Topics: Biomarkers; Biopsy; Disease Management; Disease Susceptibility; Genetic Predisposition to Disease; Hearing Loss, Sensorineural; Humans; Lymphohistiocytosis, Hemophagocytic; Mutation; Phenotype; Piebaldism; Pigmentation Disorders; Primary Immunodeficiency Diseases; Prognosis
PubMed: 33660295
DOI: 10.1111/sji.13034 -
The Journal of Investigative Dermatology Nov 2023The melanocyte-keratinocyte transplantation procedure (MKTP) treats stable and recalcitrant vitiligo. Despite careful selection of candidates based on clinical...
The melanocyte-keratinocyte transplantation procedure (MKTP) treats stable and recalcitrant vitiligo. Despite careful selection of candidates based on clinical stability, the success of the procedure is unpredictable. The aim of our study was to define the immunological profile of stable vitiligo lesions undergoing MKTP and correlate them with clinical outcomes. We included 20 MKTP candidates with vitiligo and a patient with piebaldism as a control. Prior to MKTP, T-cell subsets and chemokines in the recipient skin were measured by flow cytometry and ELISA. During MKTP, melanocytes in the donor skin were quantified by flow cytometry. After MKTP, patients were followed for 12 months and repigmentation was assessed clinically and by ImageJ analysis of clinical photographs. Baseline immunologic biomarkers, duration of clinical stability, and transplanted melanocyte number were correlated to postsurgical repigmentation scores. CD8+ T cells were elevated in 43% of the clinically stable vitiligo lesions. CD8+ T-cell number negatively correlated with postsurgical repigmentation scores (r = -0.635, P = 0.002). Duration of clinical stability, skin chemokines, and transplanted melanocyte number did not influence postsurgical repigmentation. This study demonstrates that CD8+ T-cell number correlates negatively with success of postsurgical repigmentation and can be a biomarker to identify ideal surgical candidates.
Topics: Humans; Vitiligo; Melanocytes; CD8-Positive T-Lymphocytes; Male; Female; Adult; Keratinocytes; Middle Aged; Young Adult; Treatment Outcome; Adolescent; Skin Transplantation; Follow-Up Studies
PubMed: 37478900
DOI: 10.1016/j.jid.2023.03.1689 -
American Journal of Medical Genetics.... Jun 2020Piebaldism is a rare, autosomal dominant and congenital pigmentary disorder characterized by stable depigmentation of the skin and white forelock. Mutations in KIT or...
Piebaldism is a rare, autosomal dominant and congenital pigmentary disorder characterized by stable depigmentation of the skin and white forelock. Mutations in KIT or SNAI2 genes result in piebaldism. Most individuals with piebaldism have a family history of the disorder. Herein, we report a 5-month-old Chinese girl with severe piebaldism but no family history thereof. She has white forelock and large patches of depigmentation in the jaw, central anterior trunk, perineum and extremities. We performed whole-exome and Sanger sequencing and identified a de novo KIT mutation (NM_000222.2: c.2657G>A, p.Gly886Val) in exon 18 of KIT in the proband. Currently, this mutation is located in the most extreme C-terminal of the tyrosine kinase domain 2 of the KIT gene amongst all reported mutations and causes a severe clinical phenotype. We further reviewed literature on piebaldism and summarized 79 KIT gene mutations that lead to this disease. Our study may expand knowledge on the genotype-phenotype correlation in piebaldism and serve as a reference for genetic counseling and prenatal diagnosis of affected families.
Topics: Child, Preschool; Female; Genetic Predisposition to Disease; Humans; Mutation; Pedigree; Piebaldism; Pigmentation Disorders; Proto-Oncogene Proteins c-kit; Exome Sequencing
PubMed: 32220041
DOI: 10.1002/ajmg.a.61576 -
Donor to recipient ratios in the surgical treatment of vitiligo and piebaldism: a systematic review.Journal of the European Academy of... May 2021Stabilized vitiligo resistant to conventional therapy (e.g. segmental vitiligo) and piebaldism lesions can be treated with autologous cellular grafting techniques, such...
Stabilized vitiligo resistant to conventional therapy (e.g. segmental vitiligo) and piebaldism lesions can be treated with autologous cellular grafting techniques, such as non-cultured cell suspension transplantation (NCST) and cultured melanocyte transplantation (CMT). These methods are preferred when treating larger surface areas due to the small amount of donor skin needed. However, the donor to recipient expansion ratios and outcomes reported in studies with cellular grafting vary widely, and to date, no overview or guideline exists on the optimal ratio. The aim of our study was to obtain an overview of the various expansion ratios used in cellular grafting and to identify whether expansion ratios affect repigmentation and colour match. We performed a systematic literature search in MEDLINE and EMBASE to review clinical studies that reported the expansion ratio and repigmentation after cellular grafting. We included 31 eligible clinical studies with 1591 patients in total. Our study provides an overview of various expansion ratios used in cellular grafting for vitiligo and piebaldism, which varied from 1:1 up to 1:100. We found expansion ratios between 1:1 and 1:10 for studies investigating NCST and from 1:20 to 1:100 in studies evaluating CMT. Pooled analyses of studies with the same expansion ratio and repigmentation thresholds showed that when using the lowest (1:3) expansion ratio, the proportion of lesions achieving >50% or >75% repigmentation after NCST was significantly better than when using the highest (1:10) expansion ratio (χ P = 0.000 and χ P = 0.006, respectively). Less than half of our included studies stated the colour match between different expansion ratios, and results were variable. In conclusion, the results of our study indicate that higher expansion ratios lead to lower repigmentation percentages after NCST treatment. This should be taken into consideration while determining which expansion ratio to use for treating a patient.
Topics: Humans; Melanocytes; Piebaldism; Skin Pigmentation; Skin Transplantation; Transplantation, Autologous; Treatment Outcome; Vitiligo
PubMed: 33428279
DOI: 10.1111/jdv.17108 -
Skin Research and Technology : Official... Jun 2023Piebaldism is a rare, autosomal dominant, and congenital pigmentary disorder characterized by stable depigmentation of the skin and white forelock. Mutations in KIT or...
BACKGROUND
Piebaldism is a rare, autosomal dominant, and congenital pigmentary disorder characterized by stable depigmentation of the skin and white forelock. Mutations in KIT or SLUG genes result in piebaldism. Most individuals with piebaldism have a family history of the disorder.
METHODS
In this paper, we report a case of piebaldism with café-au-lait macules resulting from a novel mutation of KIT gene c.1982C > T (p.Thr661Ile) in a three-generation Chinese family. The whole-exome sequencing, mitochondrial gene 3000X, and bioinformatics tools were used to identify the mutation in this new-found pedigree. In addition, we searched the databases of "Punmed, Chinese National Knowledge Infrastructure, CMJD, WANFANG MED ONLINE", reviewed 88 cases of piebaldism caused by KIT gene mutation, and summarized the relationship between clinical phenotype and genotype of piebaldism through logistic regression and other statistical methods.
RESULTS
The proband and her affected mother carried a heterozygous c.1982C > T missense mutation (p.Thr661Ile) on KIT gene. Bioinformatics analysis hinted that it had potential pathogenicity. The data showed that piebaldism patients with cafè-au-lait macules had KIT mutations almost located in the intracellular tyrosine kinase domain and were mostly related to the severe clinical phenotype of piebaldism.
CONCLUSION
The new heterozygous c.1982C > T missense mutation on KIT caused piebaldism with café-au-lait macules in this Chinese family. This study provides a new reference index for clinicians to judge the severity of clinical phenotypes of piebaldism, broadens the understanding of the correlation between clinical phenotypes and genotypes of piebaldism, and provides reference of genetic counseling and prenatal diagnosis for affected families.
Topics: Humans; Female; Piebaldism; Proto-Oncogene Proteins c-kit; Cafe-au-Lait Spots; Mutation; Pigmentation Disorders
PubMed: 37357653
DOI: 10.1111/srt.13352 -
Current Biology : CB Feb 2023Reptiles display great diversity in color and pattern, yet much of what we know about vertebrate coloration comes from classic model species such as the mouse and...
Reptiles display great diversity in color and pattern, yet much of what we know about vertebrate coloration comes from classic model species such as the mouse and zebrafish. Captive-bred ball pythons (Python regius) exhibit a remarkable degree of color and pattern variation. Despite the wide range of Mendelian color phenotypes available in the pet trade, ball pythons remain an overlooked species in pigmentation research. Here, we investigate the genetic basis of the recessive piebald phenotype, a pattern defect characterized by patches of unpigmented skin (leucoderma). We performed whole-genome sequencing and used a case-control approach to discover a nonsense mutation in the gene encoding the transcription factor tfec, implicating this gene in the leucodermic patches in ball pythons. We functionally validated tfec in a lizard model (Anolis sagrei) using the gene editing CRISPR/Cas9 system and TEM imaging of skin. Our findings show that reading frame mutations in tfec affect coloration and lead to a loss of iridophores in Anolis, indicating that tfec is required for chromatophore development. This study highlights the value of captive-bred ball pythons as a model species for accelerating discoveries on the genetic basis of vertebrate coloration.
Topics: Animals; Mice; Piebaldism; Zebrafish; Chromatophores; Lizards; Pigmentation; Zebrafish Proteins; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
PubMed: 36702128
DOI: 10.1016/j.cub.2023.01.004 -
Animals : An Open Access Journal From... Sep 2023Belted pig breeds have unique, distinguishing phenotypic characteristics. This review summarises the current knowledge on pig breeds displaying a belted coat pattern.... (Review)
Review
Belted pig breeds have unique, distinguishing phenotypic characteristics. This review summarises the current knowledge on pig breeds displaying a belted coat pattern. Belts of different widths and positions around the animal's trunk characterise specific pig breeds from all around the world. All the breeds included in the present paper have been searched through the FAO domestic animal diversity information system (DAD-IS), Every country was checked to identify all breeds described as having black or red piebald coat pattern variations. Advances in genomic technologies have made it possible to identify the specific genes and genetic markers associated with the belted phenotype and explore the genetic relationships between different local breeds. Thus, the origin, history, and production traits of these breeds, together with all the genomic information related to the mechanism of skin pigmentation, are discussed. By increasing our understanding of these breeds, we can appreciate the richness of our biological and cultural heritage and work to preserve the biodiversity of the world's animals.
PubMed: 37835678
DOI: 10.3390/ani13193072 -
Frontiers in Medicine 2022Piebaldism is a rare autosomal dominant disease, and roughly 75% patients had gene mutations. Up to date, approximately 90 mutations causing piebaldism were reported.
BACKGROUND
Piebaldism is a rare autosomal dominant disease, and roughly 75% patients had gene mutations. Up to date, approximately 90 mutations causing piebaldism were reported.
METHODS
To identify gene mutations in three pediatric piebaldism patients from different families and explore the genotype-phenotype correlation, peripheral blood DNA were collected from probands and their parents. Whole-exome sequencing was performed to detect potential disease-causing variants in the three probands. Putative variants were validated by Sanger sequencing.
RESULTS
Heterozygous variants of c.2469_2484del (p.Tyr823*), c.1994G > C (p.Pro665Leu), and c.1982_1983insCAT (p.662_663insIle) in gene were detected in three probands. These variants were all novel and classified as pathogenic/likely pathogenic variants according to the interpretation guidelines of American College of Medical Genetics and Genomics and the Association for Molecular Pathology. The probands carrying variants located in tyrosine kinase domain exhibited a more severe phenotype.
CONCLUSION
The piebaldism in three families was caused by novel heterozygous variants. The severity of phenotypes is related with the types and locations of different mutations. Our results further provided evidence for genetic counseling for the three families.
PubMed: 36438053
DOI: 10.3389/fmed.2022.1040747