Analysis of ocular hypopigmentation in Rab38cht/cht mice

Brian P Brooks; Denise M Larson; Chi-Chao Chan; Sten Kjellstrom; Richard S Smith; Mary A Crawford; Lynn Lamoreux; Marjan Huizing; Richard Hess; Xiaodong Jiao; J Fielding Hejtmancik; Arvydas Maminishkis; Simon W M John; Ronald A Bush; William J Pavan

doi:10.1167/iovs.06-1464

Analysis of ocular hypopigmentation in Rab38cht/cht mice

Brian P Brooks, Denise M Larson, Chi-Chao Chan, Sten Kjellstrom, Richard S Smith, Mary A Crawford, Lynn Lamoreux, Marjan Huizing, Richard Hess, Xiaodong Jiao, J Fielding Hejtmancik, Arvydas Maminishkis, Simon W M John, Ronald A Bush, William J Pavan

National Institutes of Health, United States

Research output: Contribution to journal › Article › peer-review

Abstract

PURPOSE: To characterize the ocular phenotype resulting from mutation of Rab38, a candidate gene for Hermansky-Pudlak syndrome.

METHODS: Chocolate mice (cht, Rab38(cht/cht)) and control heterozygous (Rab38(cht/)(+)) and wild-type mice were examined clinically, histologically, ultrastructurally, and electrophysiologically. Mice homozygous for both the Rab38(cht) and the Tyrp1(b) alleles were similarly examined.

RESULTS: Rab38(cht/cht) mice showed variable peripheral iris transillumination defects at 2 months of age. Patches of RPE hypopigmentation were noted clinically in 57% of Rab38(cht/cht) eyes and 6% of Rab38(cht/)(+) eyes. Rab38(cht/cht) mice exhibited thinning of the iris and RPE and larger b-wave amplitudes in the scotopic range when compared with the control animals. Compared with wild-type mice, Rab38(cht/cht) melanosomes were smaller and there were fewer in neuroectodermally derived retinal pigment epithelium; in neural crest-derived choroid melanocytes, they were smaller in size only. Mutation of both Rab38 and Tyrp1 produced mice with ocular and coat color pigment dilution greater than that seen with either mutation alone. Comprehensive clinical and pathologic analyses showed no other organ system or blood defects in Rab38(cht/cht) mice.

CONCLUSIONS: Rab38(cht/cht) mice show ocular characteristics reminiscent of human oculocutaneous albinism, as well as iris and RPE thinning. The synergistic effects of the Rab38(cht) and Tyrp1(b) alleles suggest that TYRP1 is not the only target of RAB38 trafficking. This mouse line provides a useful model for studying melanosome biology and its role in human ocular diseases.

Original language	English
Pages (from-to)	3905-13
Number of pages	9
Journal	Investigative Ophthalmology and Visual Science
Volume	48
Issue number	9
DOIs	https://doi.org/10.1167/iovs.06-1464
Publication status	Published - 2007 Sept
Externally published	Yes

Free keywords

Alleles
Animals
Blotting, Western
Choroid Diseases
Disease Models, Animal
Electroretinography
Female
Gene Expression Regulation
Hair Color
Hermanski-Pudlak Syndrome
Humans
Iris Diseases
Male
Melanosomes
Membrane Glycoproteins
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Oxidoreductases
Phenotype
Pigment Epithelium of Eye
Polymorphism, Single Nucleotide
Retinal Diseases
rab GTP-Binding Proteins
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

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10.1167/iovs.06-1464

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Brooks, B. P., Larson, D. M., Chan, C.-C., Kjellstrom, S., Smith, R. S., Crawford, M. A., Lamoreux, L., Huizing, M., Hess, R., Jiao, X., Hejtmancik, J. F., Maminishkis, A., John, S. W. M., Bush, R. A., & Pavan, W. J. (2007). Analysis of ocular hypopigmentation in Rab38cht/cht mice. Investigative Ophthalmology and Visual Science, 48(9), 3905-13. https://doi.org/10.1167/iovs.06-1464

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title = "Analysis of ocular hypopigmentation in Rab38cht/cht mice",

abstract = "PURPOSE: To characterize the ocular phenotype resulting from mutation of Rab38, a candidate gene for Hermansky-Pudlak syndrome.METHODS: Chocolate mice (cht, Rab38(cht/cht)) and control heterozygous (Rab38(cht/)(+)) and wild-type mice were examined clinically, histologically, ultrastructurally, and electrophysiologically. Mice homozygous for both the Rab38(cht) and the Tyrp1(b) alleles were similarly examined.RESULTS: Rab38(cht/cht) mice showed variable peripheral iris transillumination defects at 2 months of age. Patches of RPE hypopigmentation were noted clinically in 57% of Rab38(cht/cht) eyes and 6% of Rab38(cht/)(+) eyes. Rab38(cht/cht) mice exhibited thinning of the iris and RPE and larger b-wave amplitudes in the scotopic range when compared with the control animals. Compared with wild-type mice, Rab38(cht/cht) melanosomes were smaller and there were fewer in neuroectodermally derived retinal pigment epithelium; in neural crest-derived choroid melanocytes, they were smaller in size only. Mutation of both Rab38 and Tyrp1 produced mice with ocular and coat color pigment dilution greater than that seen with either mutation alone. Comprehensive clinical and pathologic analyses showed no other organ system or blood defects in Rab38(cht/cht) mice.CONCLUSIONS: Rab38(cht/cht) mice show ocular characteristics reminiscent of human oculocutaneous albinism, as well as iris and RPE thinning. The synergistic effects of the Rab38(cht) and Tyrp1(b) alleles suggest that TYRP1 is not the only target of RAB38 trafficking. This mouse line provides a useful model for studying melanosome biology and its role in human ocular diseases.",

keywords = "Alleles, Animals, Blotting, Western, Choroid Diseases, Disease Models, Animal, Electroretinography, Female, Gene Expression Regulation, Hair Color, Hermanski-Pudlak Syndrome, Humans, Iris Diseases, Male, Melanosomes, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Oxidoreductases, Phenotype, Pigment Epithelium of Eye, Polymorphism, Single Nucleotide, Retinal Diseases, rab GTP-Binding Proteins, Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't",

author = "Brooks, {Brian P} and Larson, {Denise M} and Chi-Chao Chan and Sten Kjellstrom and Smith, {Richard S} and Crawford, {Mary A} and Lynn Lamoreux and Marjan Huizing and Richard Hess and Xiaodong Jiao and Hejtmancik, {J Fielding} and Arvydas Maminishkis and John, {Simon W M} and Bush, {Ronald A} and Pavan, {William J}",

year = "2007",

month = sep,

doi = "10.1167/iovs.06-1464",

language = "English",

volume = "48",

pages = "3905--13",

journal = "Investigative Ophthalmology and Visual Science",

issn = "0146-0404",

publisher = "Association for Research in Vision and Ophthalmology Inc.",

number = "9",

}

TY - JOUR

T1 - Analysis of ocular hypopigmentation in Rab38cht/cht mice

AU - Brooks, Brian P

AU - Larson, Denise M

AU - Chan, Chi-Chao

AU - Kjellstrom, Sten

AU - Smith, Richard S

AU - Crawford, Mary A

AU - Lamoreux, Lynn

AU - Huizing, Marjan

AU - Hess, Richard

AU - Jiao, Xiaodong

AU - Hejtmancik, J Fielding

AU - Maminishkis, Arvydas

AU - John, Simon W M

AU - Bush, Ronald A

AU - Pavan, William J

PY - 2007/9

Y1 - 2007/9

N2 - PURPOSE: To characterize the ocular phenotype resulting from mutation of Rab38, a candidate gene for Hermansky-Pudlak syndrome.METHODS: Chocolate mice (cht, Rab38(cht/cht)) and control heterozygous (Rab38(cht/)(+)) and wild-type mice were examined clinically, histologically, ultrastructurally, and electrophysiologically. Mice homozygous for both the Rab38(cht) and the Tyrp1(b) alleles were similarly examined.RESULTS: Rab38(cht/cht) mice showed variable peripheral iris transillumination defects at 2 months of age. Patches of RPE hypopigmentation were noted clinically in 57% of Rab38(cht/cht) eyes and 6% of Rab38(cht/)(+) eyes. Rab38(cht/cht) mice exhibited thinning of the iris and RPE and larger b-wave amplitudes in the scotopic range when compared with the control animals. Compared with wild-type mice, Rab38(cht/cht) melanosomes were smaller and there were fewer in neuroectodermally derived retinal pigment epithelium; in neural crest-derived choroid melanocytes, they were smaller in size only. Mutation of both Rab38 and Tyrp1 produced mice with ocular and coat color pigment dilution greater than that seen with either mutation alone. Comprehensive clinical and pathologic analyses showed no other organ system or blood defects in Rab38(cht/cht) mice.CONCLUSIONS: Rab38(cht/cht) mice show ocular characteristics reminiscent of human oculocutaneous albinism, as well as iris and RPE thinning. The synergistic effects of the Rab38(cht) and Tyrp1(b) alleles suggest that TYRP1 is not the only target of RAB38 trafficking. This mouse line provides a useful model for studying melanosome biology and its role in human ocular diseases.

AB - PURPOSE: To characterize the ocular phenotype resulting from mutation of Rab38, a candidate gene for Hermansky-Pudlak syndrome.METHODS: Chocolate mice (cht, Rab38(cht/cht)) and control heterozygous (Rab38(cht/)(+)) and wild-type mice were examined clinically, histologically, ultrastructurally, and electrophysiologically. Mice homozygous for both the Rab38(cht) and the Tyrp1(b) alleles were similarly examined.RESULTS: Rab38(cht/cht) mice showed variable peripheral iris transillumination defects at 2 months of age. Patches of RPE hypopigmentation were noted clinically in 57% of Rab38(cht/cht) eyes and 6% of Rab38(cht/)(+) eyes. Rab38(cht/cht) mice exhibited thinning of the iris and RPE and larger b-wave amplitudes in the scotopic range when compared with the control animals. Compared with wild-type mice, Rab38(cht/cht) melanosomes were smaller and there were fewer in neuroectodermally derived retinal pigment epithelium; in neural crest-derived choroid melanocytes, they were smaller in size only. Mutation of both Rab38 and Tyrp1 produced mice with ocular and coat color pigment dilution greater than that seen with either mutation alone. Comprehensive clinical and pathologic analyses showed no other organ system or blood defects in Rab38(cht/cht) mice.CONCLUSIONS: Rab38(cht/cht) mice show ocular characteristics reminiscent of human oculocutaneous albinism, as well as iris and RPE thinning. The synergistic effects of the Rab38(cht) and Tyrp1(b) alleles suggest that TYRP1 is not the only target of RAB38 trafficking. This mouse line provides a useful model for studying melanosome biology and its role in human ocular diseases.

KW - Alleles

KW - Animals

KW - Blotting, Western

KW - Choroid Diseases

KW - Disease Models, Animal

KW - Electroretinography

KW - Female

KW - Gene Expression Regulation

KW - Hair Color

KW - Hermanski-Pudlak Syndrome

KW - Humans

KW - Iris Diseases

KW - Male

KW - Melanosomes

KW - Membrane Glycoproteins

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Mutant Strains

KW - Oxidoreductases

KW - Phenotype

KW - Pigment Epithelium of Eye

KW - Polymorphism, Single Nucleotide

KW - Retinal Diseases

KW - rab GTP-Binding Proteins

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, N.I.H., Intramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1167/iovs.06-1464

DO - 10.1167/iovs.06-1464

M3 - Article

C2 - 17724166

SN - 0146-0404

VL - 48

SP - 3905

EP - 3913

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

IS - 9

ER -

Analysis of ocular hypopigmentation in Rab38cht/cht mice

Abstract

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