Identification of a Novel MLPH Missense Mutation in a Chinese Griscelli Syndrome 3 Patient.
Identification of a Novel MLPH Missense Mutation in a Chinese Griscelli Syndrome 3 Patient.
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中国格里斯利综合征 3 患者中新型 MLPH 错义突变的鉴定
DOI：
10.3389/fmed.2022.896943
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发表时间：
2022
影响因子：
3.9
通讯作者：
中科院分区：
文献类型：
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亲黑素(MLPH)作为RAB27A和肌球蛋白Va(MYO5A)之间的连接物，在黑素小体运输过程中调节皮肤色素沉着。MYO5A-MLPH-RAB27A三元蛋白复合体需要将成熟的黑素小体锚定在黑素细胞的外周肌动蛋白细丝中，以便随后转移到邻近的角质形成细胞。Griscelli综合征3型(GS3)是由MLPH基因突变引起的。到目前为止，只有5种与GS3相关的MLPH变体被报道。在这里，我们报告了首例中国人群中的GS3患者。先证者携带一种新的纯合错义突变(c.73G>；C；p.D25H)，位于MLPH保守的SLP同源区域，表现为头发、眉毛和睫毛色素减少。光镜检查发现他的发干有异常的色素聚集。在计算机工具中，预测这种MLPH变异很可能是致病的。通过免疫印迹和免疫荧光分析，我们证明了MLPH(D25H)变异体通过在黑素细胞中表现出核周黑素小体聚集而抑制了黑素小体的转运，并极大地减少了其与RAB27A的结合，尽管患者的MLPH蛋白水平没有改变。我们的发现表明，MLPH(D25H)是一种致病变异体，它扩大了MLPH基因的遗传谱。
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.