Loss-of-Function FERMT1 Mutations in Kindler Syndrome Implicate a Role for Fermitin Family Homolog-1 in Integrin Activation

Joey E. Lai-Cheong; Maddy Parsons; Akio Tanaka; Siegfried Ussar; Andrew P. South; Sethuraman Gomathy; John B. Mee; Jean-Baptiste Barbaroux; Tanasit Techanukul; Noor Almaani; Suzanne E. Clements; Ian R. Hart; John A. McGrath

doi:10.2353/ajpath.2009.081154

Loss-of-Function FERMT1 Mutations in Kindler Syndrome Implicate a Role for Fermitin Family Homolog-1 in Integrin Activation

Joey E. Lai-Cheong, Maddy Parsons, Akio Tanaka, Siegfried Ussar, Andrew P. South, Sethuraman Gomathy, John B. Mee, Jean-Baptiste Barbaroux, Tanasit Techanukul, Noor Almaani, Suzanne E. Clements, Ian R. Hart, John A. McGrath

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Abstract

Kindler syndrome is an autosomal recessive disorder characterized by skin atrophy and blistering. It results from loss-of-function mutations in the FERMT1 gene encoding the focal adhesion protein, fermitin family homolog-1. How and why deficiency of fermitin family homolog-1 results in skin atrophy and blistering are unclear. in this study, we investigated the epidermal basement membrane and keratinocyte biology abnormalities in Kindler syndrome. We identified altered distribution of several basement membrane proteins, including types IV, VU, and XVII collagens and laminin-332 in Kindler syndrome skin. in addition, reduced immunolabeling intensity of epidermal cell markers such as beta 1 and alpha 6 integrins and cytokeratin 15 was noted. At the cellular level, there was loss of beta 4 integrin immunolocalization and random distribution of laminin-332 in Kindler syndrome keratinocytes. Of note, active beta 1 integrin was reduced but overexpression of fermitin family homolog-1 restored integrin activation and partially rescued the Kindler syndrome cellular phenotype. This study provides evidence that fermitin family homolog-1 is implicated in integrin activation and demonstrates that lack of this protein leads to pathological changes beyond focal adhesions, with disruption of several hemidesmosomal components and reduced expression of keratinocyte stein cell markers. These findings collectively provide novel data on the role of fermitin family homolog-1 in skin and further insight into the pathophysiology of Kit-idler syndrome. (Am J Pathol 2009, 175:1431-1441; DOI: 10.2353/ajpath.2009.081154)

Original language	English
Pages (from-to)	1431 - 1441
Number of pages	11
Journal	American Journal of Pathology
Volume	175
Issue number	4
DOIs	https://doi.org/10.2353/ajpath.2009.081154
Publication status	Published - 2009

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Lai-Cheong, J. E., Parsons, M., Tanaka, A., Ussar, S., South, A. P., Gomathy, S., Mee, J. B., Barbaroux, J.-B., Techanukul, T., Almaani, N., Clements, S. E., Hart, I. R., & McGrath, J. A. (2009). Loss-of-Function FERMT1 Mutations in Kindler Syndrome Implicate a Role for Fermitin Family Homolog-1 in Integrin Activation. American Journal of Pathology, 175(4), 1431 - 1441. https://doi.org/10.2353/ajpath.2009.081154

@article{d08a2a06ec5a415fbe12fa77b48c64a4,

title = "Loss-of-Function FERMT1 Mutations in Kindler Syndrome Implicate a Role for Fermitin Family Homolog-1 in Integrin Activation",

abstract = "Kindler syndrome is an autosomal recessive disorder characterized by skin atrophy and blistering. It results from loss-of-function mutations in the FERMT1 gene encoding the focal adhesion protein, fermitin family homolog-1. How and why deficiency of fermitin family homolog-1 results in skin atrophy and blistering are unclear. in this study, we investigated the epidermal basement membrane and keratinocyte biology abnormalities in Kindler syndrome. We identified altered distribution of several basement membrane proteins, including types IV, VU, and XVII collagens and laminin-332 in Kindler syndrome skin. in addition, reduced immunolabeling intensity of epidermal cell markers such as beta 1 and alpha 6 integrins and cytokeratin 15 was noted. At the cellular level, there was loss of beta 4 integrin immunolocalization and random distribution of laminin-332 in Kindler syndrome keratinocytes. Of note, active beta 1 integrin was reduced but overexpression of fermitin family homolog-1 restored integrin activation and partially rescued the Kindler syndrome cellular phenotype. This study provides evidence that fermitin family homolog-1 is implicated in integrin activation and demonstrates that lack of this protein leads to pathological changes beyond focal adhesions, with disruption of several hemidesmosomal components and reduced expression of keratinocyte stein cell markers. These findings collectively provide novel data on the role of fermitin family homolog-1 in skin and further insight into the pathophysiology of Kit-idler syndrome. (Am J Pathol 2009, 175:1431-1441; DOI: 10.2353/ajpath.2009.081154)",

author = "Lai-Cheong, {Joey E.} and Maddy Parsons and Akio Tanaka and Siegfried Ussar and South, {Andrew P.} and Sethuraman Gomathy and Mee, {John B.} and Jean-Baptiste Barbaroux and Tanasit Techanukul and Noor Almaani and Clements, {Suzanne E.} and Hart, {Ian R.} and McGrath, {John A.}",

year = "2009",

doi = "10.2353/ajpath.2009.081154",

language = "English",

volume = "175",

pages = "1431 -- 1441",

journal = "American Journal of Pathology",

publisher = "American Society for Investigative Pathology (ASIP)",

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Lai-Cheong, JE , Parsons, M , Tanaka, A, Ussar, S, South, AP, Gomathy, S, Mee, JB , Barbaroux, J-B , Techanukul, T , Almaani, N , Clements, SE, Hart, IR & McGrath, JA 2009, 'Loss-of-Function FERMT1 Mutations in Kindler Syndrome Implicate a Role for Fermitin Family Homolog-1 in Integrin Activation', American Journal of Pathology, vol. 175, no. 4, pp. 1431 - 1441. https://doi.org/10.2353/ajpath.2009.081154

TY - JOUR

T1 - Loss-of-Function FERMT1 Mutations in Kindler Syndrome Implicate a Role for Fermitin Family Homolog-1 in Integrin Activation

AU - Lai-Cheong, Joey E.

AU - Parsons, Maddy

AU - Tanaka, Akio

AU - Ussar, Siegfried

AU - South, Andrew P.

AU - Gomathy, Sethuraman

AU - Mee, John B.

AU - Barbaroux, Jean-Baptiste

AU - Techanukul, Tanasit

AU - Almaani, Noor

AU - Clements, Suzanne E.

AU - Hart, Ian R.

AU - McGrath, John A.

PY - 2009

Y1 - 2009

N2 - Kindler syndrome is an autosomal recessive disorder characterized by skin atrophy and blistering. It results from loss-of-function mutations in the FERMT1 gene encoding the focal adhesion protein, fermitin family homolog-1. How and why deficiency of fermitin family homolog-1 results in skin atrophy and blistering are unclear. in this study, we investigated the epidermal basement membrane and keratinocyte biology abnormalities in Kindler syndrome. We identified altered distribution of several basement membrane proteins, including types IV, VU, and XVII collagens and laminin-332 in Kindler syndrome skin. in addition, reduced immunolabeling intensity of epidermal cell markers such as beta 1 and alpha 6 integrins and cytokeratin 15 was noted. At the cellular level, there was loss of beta 4 integrin immunolocalization and random distribution of laminin-332 in Kindler syndrome keratinocytes. Of note, active beta 1 integrin was reduced but overexpression of fermitin family homolog-1 restored integrin activation and partially rescued the Kindler syndrome cellular phenotype. This study provides evidence that fermitin family homolog-1 is implicated in integrin activation and demonstrates that lack of this protein leads to pathological changes beyond focal adhesions, with disruption of several hemidesmosomal components and reduced expression of keratinocyte stein cell markers. These findings collectively provide novel data on the role of fermitin family homolog-1 in skin and further insight into the pathophysiology of Kit-idler syndrome. (Am J Pathol 2009, 175:1431-1441; DOI: 10.2353/ajpath.2009.081154)

AB - Kindler syndrome is an autosomal recessive disorder characterized by skin atrophy and blistering. It results from loss-of-function mutations in the FERMT1 gene encoding the focal adhesion protein, fermitin family homolog-1. How and why deficiency of fermitin family homolog-1 results in skin atrophy and blistering are unclear. in this study, we investigated the epidermal basement membrane and keratinocyte biology abnormalities in Kindler syndrome. We identified altered distribution of several basement membrane proteins, including types IV, VU, and XVII collagens and laminin-332 in Kindler syndrome skin. in addition, reduced immunolabeling intensity of epidermal cell markers such as beta 1 and alpha 6 integrins and cytokeratin 15 was noted. At the cellular level, there was loss of beta 4 integrin immunolocalization and random distribution of laminin-332 in Kindler syndrome keratinocytes. Of note, active beta 1 integrin was reduced but overexpression of fermitin family homolog-1 restored integrin activation and partially rescued the Kindler syndrome cellular phenotype. This study provides evidence that fermitin family homolog-1 is implicated in integrin activation and demonstrates that lack of this protein leads to pathological changes beyond focal adhesions, with disruption of several hemidesmosomal components and reduced expression of keratinocyte stein cell markers. These findings collectively provide novel data on the role of fermitin family homolog-1 in skin and further insight into the pathophysiology of Kit-idler syndrome. (Am J Pathol 2009, 175:1431-1441; DOI: 10.2353/ajpath.2009.081154)

U2 - 10.2353/ajpath.2009.081154

DO - 10.2353/ajpath.2009.081154

M3 - Article

VL - 175

SP - 1431

EP - 1441

JO - American Journal of Pathology

JF - American Journal of Pathology

IS - 4

ER -

Loss-of-Function FERMT1 Mutations in Kindler Syndrome Implicate a Role for Fermitin Family Homolog-1 in Integrin Activation

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