Lissencephaly associated mutations suggest a requirement for the PAFAH1B heterotrimeric complex in brain development

Kimberley J. Sweeney; Gary D. Clark; Alexander Prokscha; William B. Dobyns; Gregor Eichele

doi:10.1016/S0925-4773(00)00242-2

Lissencephaly associated mutations suggest a requirement for the PAFAH1B heterotrimeric complex in brain development

Kimberley J. Sweeney, Gary D. Clark, Alexander Prokscha, William B. Dobyns, Gregor Eichele

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42 Scopus citations

Abstract

Human brain malformations, such as Miller-Dieker syndrome (MDS) or isolated lissencephaly sequence (ILS) may result from abnormal neuronal migration during brain development. MDS and ILS patients have a hemizygous deletion or mutation in the LIS1 gene (PAFAH1B1), therefore, the LIS1 encoded protein (Lis1) may play a role in neuronal migration. Lis1 is a subunit of a brain platelet-activating factor acetylhydrolase (PAFAH1B) where it forms a heterotrimeric complex with two hydrolase subunits, referred to as 29 kDa (PAFAH1B3) and 30 kDa (PAFAH1B2). In order to determine whether this heterotrimer is required for the developmental functions of PAFAH1B, we examined the binding properties of 29 and 30 kDa subunits to mutant Lis1 proteins. The results defined the critical regions of Lis1 for PAFAH1B complex formation and demonstrated that all human LIS1 mutations examined resulted in abolished or reduced capacity of Lis1 to interact with the 29 and 30 kDa subunits, suggesting that the PAFAH1B complex participates in the process of neuronal migration. (C) 2000 Elsevier Science Ireland Ltd.

Original language	English (US)
Pages (from-to)	263-271
Number of pages	9
Journal	Mechanisms of Development
Volume	92
Issue number	2
DOIs	https://doi.org/10.1016/S0925-4773(00)00242-2
State	Published - Apr 1 2000
Externally published	Yes

Bibliographical note

Funding Information:
We wish to thank Dr Urs Albrecht for the mLis1, 29 and 30 kDa yeast two-hybrid constructs, Dr Paul James for the gift of PJ69-4A yeast cells, Uwe Grunenberg for help with sequencing and Dr Richard Lilischkis for his constant and generous advice. This work was supported by The Alexander von Humboldt Foundation (KS) and the following grants NIH NS37146 and NS38289 (GC).

Keywords

29 kDa
30 kDa
Brain development
Cortical malformation
Heterotrimeric complex
LIS1
Lissencephaly
Miller-Dieker syndrome
Mutation
Neuronal migration
PAFAH1B
PAFAH1B1
PAFAH1B2
PAFAH1B3
Platelet-activating factor
WD40 repeat protein
Yeast two-hybrid
β-Propeller structure

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title = "Lissencephaly associated mutations suggest a requirement for the PAFAH1B heterotrimeric complex in brain development",

abstract = "Human brain malformations, such as Miller-Dieker syndrome (MDS) or isolated lissencephaly sequence (ILS) may result from abnormal neuronal migration during brain development. MDS and ILS patients have a hemizygous deletion or mutation in the LIS1 gene (PAFAH1B1), therefore, the LIS1 encoded protein (Lis1) may play a role in neuronal migration. Lis1 is a subunit of a brain platelet-activating factor acetylhydrolase (PAFAH1B) where it forms a heterotrimeric complex with two hydrolase subunits, referred to as 29 kDa (PAFAH1B3) and 30 kDa (PAFAH1B2). In order to determine whether this heterotrimer is required for the developmental functions of PAFAH1B, we examined the binding properties of 29 and 30 kDa subunits to mutant Lis1 proteins. The results defined the critical regions of Lis1 for PAFAH1B complex formation and demonstrated that all human LIS1 mutations examined resulted in abolished or reduced capacity of Lis1 to interact with the 29 and 30 kDa subunits, suggesting that the PAFAH1B complex participates in the process of neuronal migration. (C) 2000 Elsevier Science Ireland Ltd.",

keywords = "29 kDa, 30 kDa, Brain development, Cortical malformation, Heterotrimeric complex, LIS1, Lissencephaly, Miller-Dieker syndrome, Mutation, Neuronal migration, PAFAH1B, PAFAH1B1, PAFAH1B2, PAFAH1B3, Platelet-activating factor, WD40 repeat protein, Yeast two-hybrid, β-Propeller structure",

author = "Sweeney, {Kimberley J.} and Clark, {Gary D.} and Alexander Prokscha and Dobyns, {William B.} and Gregor Eichele",

note = "Funding Information: We wish to thank Dr Urs Albrecht for the mLis1, 29 and 30 kDa yeast two-hybrid constructs, Dr Paul James for the gift of PJ69-4A yeast cells, Uwe Grunenberg for help with sequencing and Dr Richard Lilischkis for his constant and generous advice. This work was supported by The Alexander von Humboldt Foundation (KS) and the following grants NIH NS37146 and NS38289 (GC).",

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doi = "10.1016/S0925-4773(00)00242-2",

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T1 - Lissencephaly associated mutations suggest a requirement for the PAFAH1B heterotrimeric complex in brain development

AU - Sweeney, Kimberley J.

AU - Clark, Gary D.

AU - Prokscha, Alexander

AU - Dobyns, William B.

AU - Eichele, Gregor

N1 - Funding Information: We wish to thank Dr Urs Albrecht for the mLis1, 29 and 30 kDa yeast two-hybrid constructs, Dr Paul James for the gift of PJ69-4A yeast cells, Uwe Grunenberg for help with sequencing and Dr Richard Lilischkis for his constant and generous advice. This work was supported by The Alexander von Humboldt Foundation (KS) and the following grants NIH NS37146 and NS38289 (GC).

PY - 2000/4/1

Y1 - 2000/4/1

N2 - Human brain malformations, such as Miller-Dieker syndrome (MDS) or isolated lissencephaly sequence (ILS) may result from abnormal neuronal migration during brain development. MDS and ILS patients have a hemizygous deletion or mutation in the LIS1 gene (PAFAH1B1), therefore, the LIS1 encoded protein (Lis1) may play a role in neuronal migration. Lis1 is a subunit of a brain platelet-activating factor acetylhydrolase (PAFAH1B) where it forms a heterotrimeric complex with two hydrolase subunits, referred to as 29 kDa (PAFAH1B3) and 30 kDa (PAFAH1B2). In order to determine whether this heterotrimer is required for the developmental functions of PAFAH1B, we examined the binding properties of 29 and 30 kDa subunits to mutant Lis1 proteins. The results defined the critical regions of Lis1 for PAFAH1B complex formation and demonstrated that all human LIS1 mutations examined resulted in abolished or reduced capacity of Lis1 to interact with the 29 and 30 kDa subunits, suggesting that the PAFAH1B complex participates in the process of neuronal migration. (C) 2000 Elsevier Science Ireland Ltd.

AB - Human brain malformations, such as Miller-Dieker syndrome (MDS) or isolated lissencephaly sequence (ILS) may result from abnormal neuronal migration during brain development. MDS and ILS patients have a hemizygous deletion or mutation in the LIS1 gene (PAFAH1B1), therefore, the LIS1 encoded protein (Lis1) may play a role in neuronal migration. Lis1 is a subunit of a brain platelet-activating factor acetylhydrolase (PAFAH1B) where it forms a heterotrimeric complex with two hydrolase subunits, referred to as 29 kDa (PAFAH1B3) and 30 kDa (PAFAH1B2). In order to determine whether this heterotrimer is required for the developmental functions of PAFAH1B, we examined the binding properties of 29 and 30 kDa subunits to mutant Lis1 proteins. The results defined the critical regions of Lis1 for PAFAH1B complex formation and demonstrated that all human LIS1 mutations examined resulted in abolished or reduced capacity of Lis1 to interact with the 29 and 30 kDa subunits, suggesting that the PAFAH1B complex participates in the process of neuronal migration. (C) 2000 Elsevier Science Ireland Ltd.

KW - 29 kDa

KW - 30 kDa

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KW - Heterotrimeric complex

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KW - Miller-Dieker syndrome

KW - Mutation

KW - Neuronal migration

KW - PAFAH1B

KW - PAFAH1B1

KW - PAFAH1B2

KW - PAFAH1B3

KW - Platelet-activating factor

KW - WD40 repeat protein

KW - Yeast two-hybrid

KW - β-Propeller structure

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M3 - Article

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AN - SCOPUS:0034176845

SN - 0925-4773

VL - 92

SP - 263

EP - 271

JO - Mechanisms of Development

JF - Mechanisms of Development

IS - 2

ER -

Lissencephaly associated mutations suggest a requirement for the PAFAH1B heterotrimeric complex in brain development

Abstract

Bibliographical note

Keywords

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