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Novel mutations of ABCB6 associated with autosomal dominant dyschromatosis universalis hereditaria.

Cui YX, Xia XY, Zhou Y, Gao L, Shang XJ, Ni T, Wang WP, Fan XB, Yin HL, Jiang SJ, Yao B, Hu YA, Wang G, Li XJ - PLoS ONE (2013)

Bottom Line: Empty immature melanosomes were found in the hypopigmented melanocytes.An additional mutation (g.776 delC, c.459 delC) in ABCB6 was found in an unrelated sporadic patient.Our data add new variants to the repertoire of ABCB6 mutations with DUH.

View Article: PubMed Central - PubMed

Affiliation: Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, PR China.

ABSTRACT

Objective: Dyschromatosis universalis hereditaria (DUH) is a rare heterogeneous pigmentary genodermatosis, which was first described in 1933. The genetic cause has recently been discovered by the discovery of mutations in ABCB6. Here we investigated a Chinese family with typical features of autosomal dominant DUH and 3 unrelated patients with sporadic DUH.

Methods: Skin tissues were obtained from the proband, of this family and the 3 sporadic patients. Histopathological examination and immunohistochemical analysis of ABCB6 were performed. Peripheral blood DNA samples were obtained from 21 affected, 14 unaffected, 11 spouses in the family and the 3 sporadic patients. A genome-wide linkage scan for the family was carried out to localize the causative gene. Exome sequencing was performed from 3 affected and 1 unaffected in the family. Sanger sequencing of ABCB6 was further used to identify the causative gene for all samples obtained from available family members, the 3 sporadic patients and a panel of 455 ethnically-matched normal Chinese individuals.

Results: Histopathological analysis showed melanocytes in normal control's skin tissue and the hyperpigmented area contained more melanized, mature melanosomes than those within the hypopigmented areas. Empty immature melanosomes were found in the hypopigmented melanocytes. Parametric multipoint linkage analysis produced a HLOD score of 4.68, with markers on chromosome 2q35-q37.2. A missense mutation (c.1663 C>A, p.Gln555Lys) in ABCB6 was identified in this family by exome and Sanger sequencing. The mutation perfectly cosegregated with the skin phenotype. An additional mutation (g.776 delC, c.459 delC) in ABCB6 was found in an unrelated sporadic patient. No mutation in ABCB6 was discovered in the other two sporadic patients. Neither of the two mutations was present in the 455 controls. Melanocytes showed positive immunoreactivity to ABCB6.

Conclusion: Our data add new variants to the repertoire of ABCB6 mutations with DUH.

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Related in: MedlinePlus

Skin histological examination under light and electron microscopy.(A-C) Sections of skin cutaneous tissues by methylene blue staining from the normal control, from the proband’s hyperpigmented area, from the proband’s hypopigmented area observed under light microscopy. (D-F) A melanocyte from the normal control’ skin tissue, from the proband’s hyperpigmented and from hypopigmented skin tissues observed by electron microscopy. (G-I) Melanosomes in the normal control’ melanocyte, in proband’s hyperpigmented and in hypopigmented melanocytes observed by electron microscopy. (B-C) Methylene blue staining of cutaneous tissues shows normal numbers of morphologically-intact melanocytes present in the basal layer of hypo- and hyper-pigmented skin areas. The content and distribution of mature melanosomes in hyperpigmented macules(E) were similar to as in the normal control(D), whereas the content in hypo-pigmented macule(F) was less than in the normal control(D). (G-H) Mature melanosomes in a melanocyte from the normal control’ tissue, from the proband’s hyperpigmented area. (I) Empty immature melanosomes in the stage II in a hypopigmented melanocyte. Arrows indicate melanocytes or melanosomes.
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pone-0079808-g002: Skin histological examination under light and electron microscopy.(A-C) Sections of skin cutaneous tissues by methylene blue staining from the normal control, from the proband’s hyperpigmented area, from the proband’s hypopigmented area observed under light microscopy. (D-F) A melanocyte from the normal control’ skin tissue, from the proband’s hyperpigmented and from hypopigmented skin tissues observed by electron microscopy. (G-I) Melanosomes in the normal control’ melanocyte, in proband’s hyperpigmented and in hypopigmented melanocytes observed by electron microscopy. (B-C) Methylene blue staining of cutaneous tissues shows normal numbers of morphologically-intact melanocytes present in the basal layer of hypo- and hyper-pigmented skin areas. The content and distribution of mature melanosomes in hyperpigmented macules(E) were similar to as in the normal control(D), whereas the content in hypo-pigmented macule(F) was less than in the normal control(D). (G-H) Mature melanosomes in a melanocyte from the normal control’ tissue, from the proband’s hyperpigmented area. (I) Empty immature melanosomes in the stage II in a hypopigmented melanocyte. Arrows indicate melanocytes or melanosomes.

Mentions: A normal number of morphologically-intact melanocytes were present in the basal layer in hypo- and hyper-pigmented skin areas from the proband (Figure 2B-C). Histopathologic analysis showed melanocytes in normal control’s skin tissue (Figure 2A, D, G) and the hyperpigmented areas from the proband (Figure 2B, E, H) contained more melanin or melanized, mature melanosomes than those within the hypopigmented areas (Figure 2C, F, I). Empty immature melanosomes were found in the hypopigmented melanocytes (Figure 2I). Comparing the content and distribution of mature melanosomes in melanocytes from the proband with those from the normal control, we found the content and distribution in hyperpigmented macule (Figure 2E) were similar to normal control (Figure 2D), whereas the content in hypo-pigmented macule (Figure 2F) was less than control (Figure 2D).


Novel mutations of ABCB6 associated with autosomal dominant dyschromatosis universalis hereditaria.

Cui YX, Xia XY, Zhou Y, Gao L, Shang XJ, Ni T, Wang WP, Fan XB, Yin HL, Jiang SJ, Yao B, Hu YA, Wang G, Li XJ - PLoS ONE (2013)

Skin histological examination under light and electron microscopy.(A-C) Sections of skin cutaneous tissues by methylene blue staining from the normal control, from the proband’s hyperpigmented area, from the proband’s hypopigmented area observed under light microscopy. (D-F) A melanocyte from the normal control’ skin tissue, from the proband’s hyperpigmented and from hypopigmented skin tissues observed by electron microscopy. (G-I) Melanosomes in the normal control’ melanocyte, in proband’s hyperpigmented and in hypopigmented melanocytes observed by electron microscopy. (B-C) Methylene blue staining of cutaneous tissues shows normal numbers of morphologically-intact melanocytes present in the basal layer of hypo- and hyper-pigmented skin areas. The content and distribution of mature melanosomes in hyperpigmented macules(E) were similar to as in the normal control(D), whereas the content in hypo-pigmented macule(F) was less than in the normal control(D). (G-H) Mature melanosomes in a melanocyte from the normal control’ tissue, from the proband’s hyperpigmented area. (I) Empty immature melanosomes in the stage II in a hypopigmented melanocyte. Arrows indicate melanocytes or melanosomes.
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Related In: Results  -  Collection

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pone-0079808-g002: Skin histological examination under light and electron microscopy.(A-C) Sections of skin cutaneous tissues by methylene blue staining from the normal control, from the proband’s hyperpigmented area, from the proband’s hypopigmented area observed under light microscopy. (D-F) A melanocyte from the normal control’ skin tissue, from the proband’s hyperpigmented and from hypopigmented skin tissues observed by electron microscopy. (G-I) Melanosomes in the normal control’ melanocyte, in proband’s hyperpigmented and in hypopigmented melanocytes observed by electron microscopy. (B-C) Methylene blue staining of cutaneous tissues shows normal numbers of morphologically-intact melanocytes present in the basal layer of hypo- and hyper-pigmented skin areas. The content and distribution of mature melanosomes in hyperpigmented macules(E) were similar to as in the normal control(D), whereas the content in hypo-pigmented macule(F) was less than in the normal control(D). (G-H) Mature melanosomes in a melanocyte from the normal control’ tissue, from the proband’s hyperpigmented area. (I) Empty immature melanosomes in the stage II in a hypopigmented melanocyte. Arrows indicate melanocytes or melanosomes.
Mentions: A normal number of morphologically-intact melanocytes were present in the basal layer in hypo- and hyper-pigmented skin areas from the proband (Figure 2B-C). Histopathologic analysis showed melanocytes in normal control’s skin tissue (Figure 2A, D, G) and the hyperpigmented areas from the proband (Figure 2B, E, H) contained more melanin or melanized, mature melanosomes than those within the hypopigmented areas (Figure 2C, F, I). Empty immature melanosomes were found in the hypopigmented melanocytes (Figure 2I). Comparing the content and distribution of mature melanosomes in melanocytes from the proband with those from the normal control, we found the content and distribution in hyperpigmented macule (Figure 2E) were similar to normal control (Figure 2D), whereas the content in hypo-pigmented macule (Figure 2F) was less than control (Figure 2D).

Bottom Line: Empty immature melanosomes were found in the hypopigmented melanocytes.An additional mutation (g.776 delC, c.459 delC) in ABCB6 was found in an unrelated sporadic patient.Our data add new variants to the repertoire of ABCB6 mutations with DUH.

View Article: PubMed Central - PubMed

Affiliation: Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, PR China.

ABSTRACT

Objective: Dyschromatosis universalis hereditaria (DUH) is a rare heterogeneous pigmentary genodermatosis, which was first described in 1933. The genetic cause has recently been discovered by the discovery of mutations in ABCB6. Here we investigated a Chinese family with typical features of autosomal dominant DUH and 3 unrelated patients with sporadic DUH.

Methods: Skin tissues were obtained from the proband, of this family and the 3 sporadic patients. Histopathological examination and immunohistochemical analysis of ABCB6 were performed. Peripheral blood DNA samples were obtained from 21 affected, 14 unaffected, 11 spouses in the family and the 3 sporadic patients. A genome-wide linkage scan for the family was carried out to localize the causative gene. Exome sequencing was performed from 3 affected and 1 unaffected in the family. Sanger sequencing of ABCB6 was further used to identify the causative gene for all samples obtained from available family members, the 3 sporadic patients and a panel of 455 ethnically-matched normal Chinese individuals.

Results: Histopathological analysis showed melanocytes in normal control's skin tissue and the hyperpigmented area contained more melanized, mature melanosomes than those within the hypopigmented areas. Empty immature melanosomes were found in the hypopigmented melanocytes. Parametric multipoint linkage analysis produced a HLOD score of 4.68, with markers on chromosome 2q35-q37.2. A missense mutation (c.1663 C>A, p.Gln555Lys) in ABCB6 was identified in this family by exome and Sanger sequencing. The mutation perfectly cosegregated with the skin phenotype. An additional mutation (g.776 delC, c.459 delC) in ABCB6 was found in an unrelated sporadic patient. No mutation in ABCB6 was discovered in the other two sporadic patients. Neither of the two mutations was present in the 455 controls. Melanocytes showed positive immunoreactivity to ABCB6.

Conclusion: Our data add new variants to the repertoire of ABCB6 mutations with DUH.

Show MeSH
Related in: MedlinePlus