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Identification of a Novel MLPH Missense Mutation in a Chinese Griscelli Syndrome 3 Patient

Melanophilin (MLPH) functions as a linker between RAB27A and myosin Va (MYO5A) in regulating skin pigmentation during the melanosome transport process. The MYO5A-MLPH-RAB27A ternary protein complex is required for anchoring mature melanosomes in the peripheral actin filaments of melanocytes for subs...

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Autores principales: Huang, Qiaorong, Yuan, Yefeng, Gong, Juanjuan, Zhang, Tianjiao, Qi, Zhan, Yang, Xiumin, Li, Wei, Wei, Aihua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120966/
https://www.ncbi.nlm.nih.gov/pubmed/35602484
http://dx.doi.org/10.3389/fmed.2022.896943
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author Huang, Qiaorong
Yuan, Yefeng
Gong, Juanjuan
Zhang, Tianjiao
Qi, Zhan
Yang, Xiumin
Li, Wei
Wei, Aihua
author_facet Huang, Qiaorong
Yuan, Yefeng
Gong, Juanjuan
Zhang, Tianjiao
Qi, Zhan
Yang, Xiumin
Li, Wei
Wei, Aihua
author_sort Huang, Qiaorong
collection PubMed
description Melanophilin (MLPH) functions as a linker between RAB27A and myosin Va (MYO5A) in regulating skin pigmentation during the melanosome transport process. The MYO5A-MLPH-RAB27A ternary protein complex is required for anchoring mature melanosomes in the peripheral actin filaments of melanocytes for subsequent transfer to adjacent keratinocytes. Griscelli syndrome type 3 (GS3) is caused by mutations in the MLPH gene. So far, only five variants of MLPH associated with GS3 have been reported. Here, we reported the first patient with GS3 in a Chinese population. The proband carried a novel homozygous missense mutation (c.73G>C; p.D25H), residing in the conserved Slp homology domain of MLPH, and presented with hypopigmentation of the hair, eyebrows, and eyelashes. Light microscopy revealed the presence of abnormal pigment clumping in his hair shaft. In silico tools predicted this MLPH variant to be likely pathogenic. Using immunoblotting and immunofluorescence analysis, we demonstrated that the MLPH (D25H) variant had an inhibitory effect on melanosome transport by exhibiting perinuclear melanosome aggregation in melanocytes, and greatly reduced its binding to RAB27A, although the protein level of MLPH in the patient was not changed. Our findings suggest that MLPH (D25H) is a pathogenic variant that expands the genetic spectrum of the MLPH gene.
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spelling pubmed-91209662022-05-21 Identification of a Novel MLPH Missense Mutation in a Chinese Griscelli Syndrome 3 Patient Huang, Qiaorong Yuan, Yefeng Gong, Juanjuan Zhang, Tianjiao Qi, Zhan Yang, Xiumin Li, Wei Wei, Aihua Front Med (Lausanne) Medicine Melanophilin (MLPH) functions as a linker between RAB27A and myosin Va (MYO5A) in regulating skin pigmentation during the melanosome transport process. The MYO5A-MLPH-RAB27A ternary protein complex is required for anchoring mature melanosomes in the peripheral actin filaments of melanocytes for subsequent transfer to adjacent keratinocytes. Griscelli syndrome type 3 (GS3) is caused by mutations in the MLPH gene. So far, only five variants of MLPH associated with GS3 have been reported. Here, we reported the first patient with GS3 in a Chinese population. The proband carried a novel homozygous missense mutation (c.73G>C; p.D25H), residing in the conserved Slp homology domain of MLPH, and presented with hypopigmentation of the hair, eyebrows, and eyelashes. Light microscopy revealed the presence of abnormal pigment clumping in his hair shaft. In silico tools predicted this MLPH variant to be likely pathogenic. Using immunoblotting and immunofluorescence analysis, we demonstrated that the MLPH (D25H) variant had an inhibitory effect on melanosome transport by exhibiting perinuclear melanosome aggregation in melanocytes, and greatly reduced its binding to RAB27A, although the protein level of MLPH in the patient was not changed. Our findings suggest that MLPH (D25H) is a pathogenic variant that expands the genetic spectrum of the MLPH gene. Frontiers Media S.A. 2022-05-06 /pmc/articles/PMC9120966/ /pubmed/35602484 http://dx.doi.org/10.3389/fmed.2022.896943 Text en Copyright © 2022 Huang, Yuan, Gong, Zhang, Qi, Yang, Li and Wei. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Huang, Qiaorong
Yuan, Yefeng
Gong, Juanjuan
Zhang, Tianjiao
Qi, Zhan
Yang, Xiumin
Li, Wei
Wei, Aihua
Identification of a Novel MLPH Missense Mutation in a Chinese Griscelli Syndrome 3 Patient
title Identification of a Novel MLPH Missense Mutation in a Chinese Griscelli Syndrome 3 Patient
title_full Identification of a Novel MLPH Missense Mutation in a Chinese Griscelli Syndrome 3 Patient
title_fullStr Identification of a Novel MLPH Missense Mutation in a Chinese Griscelli Syndrome 3 Patient
title_full_unstemmed Identification of a Novel MLPH Missense Mutation in a Chinese Griscelli Syndrome 3 Patient
title_short Identification of a Novel MLPH Missense Mutation in a Chinese Griscelli Syndrome 3 Patient
title_sort identification of a novel mlph missense mutation in a chinese griscelli syndrome 3 patient
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120966/
https://www.ncbi.nlm.nih.gov/pubmed/35602484
http://dx.doi.org/10.3389/fmed.2022.896943
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