Mutations in the Cholesterol Transporter Gene ABCA5 Are Associated with Excessive Hair Overgrowth

Gina M. DeStefano, Mazen Kurban, Kwame Anyane-Yeboa, Claudia Dall'Armi, Gilbert Di Paolo, Heather Feenstra, Nanette Silverberg, Luis Rohena, Larissa D. López-Cepeda, Vaidehi Jobanputra, Katherine A. Fantauzzo, Maija Kiuru, Marija Tadin-Strapps, Antonio Sobrino, Anna Vitebsky, Dorothy Warburton, Brynn Levy, Julio C. Salas-Alanis, Angela M. Christiano

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Inherited hypertrichoses are rare syndromes characterized by excessive hair growth that does not result from androgen stimulation, and are often associated with additional congenital abnormalities. In this study, we investigated the genetic defect in a case of autosomal recessive congenital generalized hypertrichosis terminalis (CGHT) (OMIM135400) using whole-exome sequencing. We identified a single base pair substitution in the 5′ donor splice site of intron 32 in the ABC lipid transporter gene ABCA5 that leads to aberrant splicing of the transcript and a decrease in protein levels throughout patient hair follicles. The homozygous recessive disruption of ABCA5 leads to reduced lysosome function, which results in an accumulation of autophagosomes, autophagosomal cargos as well as increased endolysosomal cholesterol in CGHT keratinocytes. In an unrelated sporadic case of CGHT, we identified a 1.3 Mb cryptic deletion of chr17q24.2-q24.3 encompassing ABCA5 and found that ABCA5 levels are dramatically reduced throughout patient hair follicles. Collectively, our findings support ABCA5 as a gene underlying the CGHT phenotype and suggest a novel, previously unrecognized role for this gene in regulating hair growth. © 2014 DeStefano et al.
Original languageEnglish
JournalPLoS Genetics
DOIs
Publication statusPublished - 1 Jan 2014

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hair
Hair
hairs
transporters
mutation
hair follicles
Cholesterol
cholesterol
Mutation
Hair Follicle
gene
congenital abnormalities
Genes
genes
keratinocytes
lysosomes
genetic disorders
androgens
Exome
RNA Splice Sites

Cite this

DeStefano, G. M., Kurban, M., Anyane-Yeboa, K., Dall'Armi, C., Di Paolo, G., Feenstra, H., ... Christiano, A. M. (2014). Mutations in the Cholesterol Transporter Gene ABCA5 Are Associated with Excessive Hair Overgrowth. PLoS Genetics. https://doi.org/10.1371/journal.pgen.1004333
DeStefano, Gina M. ; Kurban, Mazen ; Anyane-Yeboa, Kwame ; Dall'Armi, Claudia ; Di Paolo, Gilbert ; Feenstra, Heather ; Silverberg, Nanette ; Rohena, Luis ; López-Cepeda, Larissa D. ; Jobanputra, Vaidehi ; Fantauzzo, Katherine A. ; Kiuru, Maija ; Tadin-Strapps, Marija ; Sobrino, Antonio ; Vitebsky, Anna ; Warburton, Dorothy ; Levy, Brynn ; Salas-Alanis, Julio C. ; Christiano, Angela M. / Mutations in the Cholesterol Transporter Gene ABCA5 Are Associated with Excessive Hair Overgrowth. In: PLoS Genetics. 2014.
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abstract = "Inherited hypertrichoses are rare syndromes characterized by excessive hair growth that does not result from androgen stimulation, and are often associated with additional congenital abnormalities. In this study, we investigated the genetic defect in a case of autosomal recessive congenital generalized hypertrichosis terminalis (CGHT) (OMIM135400) using whole-exome sequencing. We identified a single base pair substitution in the 5′ donor splice site of intron 32 in the ABC lipid transporter gene ABCA5 that leads to aberrant splicing of the transcript and a decrease in protein levels throughout patient hair follicles. The homozygous recessive disruption of ABCA5 leads to reduced lysosome function, which results in an accumulation of autophagosomes, autophagosomal cargos as well as increased endolysosomal cholesterol in CGHT keratinocytes. In an unrelated sporadic case of CGHT, we identified a 1.3 Mb cryptic deletion of chr17q24.2-q24.3 encompassing ABCA5 and found that ABCA5 levels are dramatically reduced throughout patient hair follicles. Collectively, our findings support ABCA5 as a gene underlying the CGHT phenotype and suggest a novel, previously unrecognized role for this gene in regulating hair growth. {\circledC} 2014 DeStefano et al.",
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DeStefano, GM, Kurban, M, Anyane-Yeboa, K, Dall'Armi, C, Di Paolo, G, Feenstra, H, Silverberg, N, Rohena, L, López-Cepeda, LD, Jobanputra, V, Fantauzzo, KA, Kiuru, M, Tadin-Strapps, M, Sobrino, A, Vitebsky, A, Warburton, D, Levy, B, Salas-Alanis, JC & Christiano, AM 2014, 'Mutations in the Cholesterol Transporter Gene ABCA5 Are Associated with Excessive Hair Overgrowth', PLoS Genetics. https://doi.org/10.1371/journal.pgen.1004333

Mutations in the Cholesterol Transporter Gene ABCA5 Are Associated with Excessive Hair Overgrowth. / DeStefano, Gina M.; Kurban, Mazen; Anyane-Yeboa, Kwame; Dall'Armi, Claudia; Di Paolo, Gilbert; Feenstra, Heather; Silverberg, Nanette; Rohena, Luis; López-Cepeda, Larissa D.; Jobanputra, Vaidehi; Fantauzzo, Katherine A.; Kiuru, Maija; Tadin-Strapps, Marija; Sobrino, Antonio; Vitebsky, Anna; Warburton, Dorothy; Levy, Brynn; Salas-Alanis, Julio C.; Christiano, Angela M.

In: PLoS Genetics, 01.01.2014.

Research output: Contribution to journalArticle

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T1 - Mutations in the Cholesterol Transporter Gene ABCA5 Are Associated with Excessive Hair Overgrowth

AU - DeStefano, Gina M.

AU - Kurban, Mazen

AU - Anyane-Yeboa, Kwame

AU - Dall'Armi, Claudia

AU - Di Paolo, Gilbert

AU - Feenstra, Heather

AU - Silverberg, Nanette

AU - Rohena, Luis

AU - López-Cepeda, Larissa D.

AU - Jobanputra, Vaidehi

AU - Fantauzzo, Katherine A.

AU - Kiuru, Maija

AU - Tadin-Strapps, Marija

AU - Sobrino, Antonio

AU - Vitebsky, Anna

AU - Warburton, Dorothy

AU - Levy, Brynn

AU - Salas-Alanis, Julio C.

AU - Christiano, Angela M.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Inherited hypertrichoses are rare syndromes characterized by excessive hair growth that does not result from androgen stimulation, and are often associated with additional congenital abnormalities. In this study, we investigated the genetic defect in a case of autosomal recessive congenital generalized hypertrichosis terminalis (CGHT) (OMIM135400) using whole-exome sequencing. We identified a single base pair substitution in the 5′ donor splice site of intron 32 in the ABC lipid transporter gene ABCA5 that leads to aberrant splicing of the transcript and a decrease in protein levels throughout patient hair follicles. The homozygous recessive disruption of ABCA5 leads to reduced lysosome function, which results in an accumulation of autophagosomes, autophagosomal cargos as well as increased endolysosomal cholesterol in CGHT keratinocytes. In an unrelated sporadic case of CGHT, we identified a 1.3 Mb cryptic deletion of chr17q24.2-q24.3 encompassing ABCA5 and found that ABCA5 levels are dramatically reduced throughout patient hair follicles. Collectively, our findings support ABCA5 as a gene underlying the CGHT phenotype and suggest a novel, previously unrecognized role for this gene in regulating hair growth. © 2014 DeStefano et al.

AB - Inherited hypertrichoses are rare syndromes characterized by excessive hair growth that does not result from androgen stimulation, and are often associated with additional congenital abnormalities. In this study, we investigated the genetic defect in a case of autosomal recessive congenital generalized hypertrichosis terminalis (CGHT) (OMIM135400) using whole-exome sequencing. We identified a single base pair substitution in the 5′ donor splice site of intron 32 in the ABC lipid transporter gene ABCA5 that leads to aberrant splicing of the transcript and a decrease in protein levels throughout patient hair follicles. The homozygous recessive disruption of ABCA5 leads to reduced lysosome function, which results in an accumulation of autophagosomes, autophagosomal cargos as well as increased endolysosomal cholesterol in CGHT keratinocytes. In an unrelated sporadic case of CGHT, we identified a 1.3 Mb cryptic deletion of chr17q24.2-q24.3 encompassing ABCA5 and found that ABCA5 levels are dramatically reduced throughout patient hair follicles. Collectively, our findings support ABCA5 as a gene underlying the CGHT phenotype and suggest a novel, previously unrecognized role for this gene in regulating hair growth. © 2014 DeStefano et al.

U2 - 10.1371/journal.pgen.1004333

DO - 10.1371/journal.pgen.1004333

M3 - Article

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

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