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J Med Genet. 2012 Mar;49(3):179-83. doi: 10.1136/jmedgenet-2011-100542.

Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects.

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1
Radboud University Nijmegen Medical Centre, Department of Human Genetics, Nijmegen, The Netherlands.

Abstract

BACKGROUND:

DYNC1H1 encodes the heavy chain protein of the cytoplasmic dynein 1 motor protein complex that plays a key role in retrograde axonal transport in neurons. Furthermore, it interacts with the LIS1 gene of which haploinsufficiency causes a severe neuronal migration disorder in humans, known as classical lissencephaly or Miller-Dieker syndrome.

AIM:

To describe the clinical spectrum and molecular characteristics of DYNC1H1 mutations.

METHODS:

A family based exome sequencing approach was used to identify de novo mutations in patients with severe intellectual disability.

RESULTS:

In this report the identification of two de novo missense mutations in DYNC1H1 (p.Glu1518Lys and p.His3822Pro) in two patients with severe intellectual disability and variable neuronal migration defects is described.

CONCLUSION:

Since an autosomal dominant mutation in DYNC1H1 was previously identified in a family with the axonal (type 2) form of Charcot- Marie-Tooth (CMT2) disease and mutations in Dync1h1 in mice also cause impaired neuronal migration in addition to neuropathy, these data together suggest that mutations in DYNC1H1 can lead to a broad phenotypic spectrum and confirm the importance of DYNC1H1 in both central and peripheral neuronal functions.

PMID:
22368300
DOI:
10.1136/jmedgenet-2011-100542
[Indexed for MEDLINE]
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