The Very Low Density Lipoprotein Receptor–Associated Pontocerebellar Hypoplasia and Dysmorphic Features in Three Turkish Patients

Abstract

Pontocerebellar hypoplasia consists of a rare heterogeneous group of congenital neurodevelopmental disorders characterized by hypoplasia and atrophy of the cerebellar cortex, dentate and pontine nuclei, and inferior olives. The very low density lipoprotein receptor protein is an integral part of the reelin signaling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum. Mutations in this receptor cause nonprogressive cerebellar ataxia, mental retardation, and cerebellar hypoplasia. In this report, we present 3 patients from 2 different families displaying very low density lipoprotein receptor–associated pontocerebellar hypoplasia, cortical dysplasia, mental retardation, and bipedal gait. One of the siblings has also displayed dysmorphic features, as we previously reported before the identification of the genetic defect in this family.

Keywords

pontocerebellar hypoplasia VLDLR mutation dysmorphic features reelin

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References

Boycott

Flavelle

Bureau

Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification. Am J Hum Genet. 2005;77:477–483.

Ozcelik

Akarsu

Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadripedal locomoton in humans. Proc Natl Acad Sci U S A. 2008;105:4232–4236.

Moheb

Tzschach

Garshasbi

Identification of a nonsense mutation in the very low-density lipoprotein receptor gene (VLDLR) in an Iranian family with dysequilibrium syndrome. Eur J Hum Genet. 2008;16:270–273.

Boycott

Parboosingh

. VLDLR-associated cerebellar hypoplasia. In: Pagon

Bird

Dalan

Stephens

, eds. Gene Reviews (Internet). Seattle, WA: University of Washington;1993–2008.

Boycott

Bonnemann

Herz

Mutations in VLDLR as a cause for autosomal recessive cerebellar ataxia with metal retardation (dysequilibrium syndrome). J Child Neurol. 2009;24:1310–1315.

Turkmen

Hoffmann

Demirhan

Aruoba

Humphrey

Mundlos

. Cerebellar hypoplasia, with quadripedal locomotion, caused by mutations in the very low-density lipoprotein receptor gene. Eur J Hum Genet. 2008;16:1070–1074.

Kolb

Arlier

Yalcinkaya

Novel VLDLR microdeletion identified in two Turkish siblings with pachygyria and pontocerebellar atrophy. Neurogenetics. 2010;11:319–325.

Strickland

Kounnas

Argraves

. LDL receptor-related protein: a multiligand receptor for lipoprotein and proteinase catabolism. FASEB J. 1995;9:890–898.

Sakai

Hoshino

Takahashi

Structure, chromosome location and expression of the human very low-density lipoprotein receptor gene. J Biol Chem. 1994;269:2173–2182.

10.

Takahashi

Suzuki

Kohno

Enhancement of the binding of triglyceride-rich lipoproteins to the very low-density lipoprotein receptor by apolipoprotein E and lipoprotein lipase. J Biol Chem. 1995;270:15747–15754.

11.

Dilber

Aynaci

Ahmetoglu

. Pontocerebellar hypoplasia in two siblings with dysmorphic features. J Child Neurol. 2002;17:64–66.

12.

Tissir

Gofinet

. Reelin and brain development. Nat Rev Neurosci. 2003;4:496–505.

13.

Hiesberger

Trommsdorff

Howell

Direct binding of reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron. 1999;24:481–489.

14.

Zaki

Shehab

El-Aleem

Identification of a novel recessive RELN mutation using a homozygous balanced reciprocal translocation. Am J Med Genet. 2007;143A:939–944.

15.

DeSilva

D'Arcangelo

Braden

The human reelin gene: isolation, sequencing, and mapping on chromosome 7. Genome Res. 1997;7:157–164.

16.

Tan

. A new syndrome with quadripedal gait, primitive speech, and severe mental retardation as a live model for human evolution. Int J Neurosci. 2006;116:361–369.