Contribution of CYLN2 and GTF2IRD1 to neurological and cognitive symptoms in Williams Syndrome

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Abstract

Williams Syndrome (WS, [MIM 194050]) is a disorder caused by a hemizygous deletion of 25–30 genes on chromosome 7q11.23. Several of these genes including those encoding cytoplasmic linker protein-115 (CYLN2) and general transcription factors (GTF2I and GTF2IRD1) are expressed in the brain and may contribute to the distinct neurological and cognitive deficits in WS patients. Recent studies of patients with partial deletions indicate that hemizygosity of GTF2I probably contributes to mental retardation in WS. Here we investigate whether CYLN2 and GTF2IRD1 contribute to the motoric and cognitive deficits in WS. Behavioral assessment of a new patient in which STX1A and LIMK1, but not CYLN2 and GTF2IRD1, are deleted showed that his cognitive and motor coordination functions were significantly better than in typical WS patients. Comparative analyses of gene specific CYLN2 and GTF2IRD1 knockout mice showed that a reduced size of the corpus callosum as well as deficits in motor coordination and hippocampal memory formation may be attributed to a deletion of CYLN2, while increased ventricle volume can be attributed to both CYLN2 and GTF2IRD1. We conclude that the motor and cognitive deficits in Williams Syndrome are caused by a variety of genes and that heterozygous deletion of CYLN2 is one of the major causes responsible for such dysfunctions.

Introduction

Williams Syndrome (WS, also known as Williams–Beuren syndrome, MIM 194050) is a genetically determined neurodevelopmental disorder, which is characterized by a rather unique combination of distinct facial features and medical complications on the one hand and characteristic behavioral patterns and cognitive disabilities on the other hand (for reviews see, e.g., Bellugi et al., 1999, Morris and Mervis, 2000, Mervis, 2003, Tassabehji, 2003). The facial features include a broad nasal tip, a long philtrum and full cheeks and lips, while the medical complications are dominated by supravalvular aortic stenosis (SVAS) and pulmonary arterial stenosis (PAS), growth retardation, intermittent hypercalcemia, hyperacusis and dental abnormalities. The behavioral and cognitive abnormalities are also reflected in a wide variety of symptoms including abnormal gait, impaired stair and surface stepping, dysmetria of saccadic eye movements, a low mean IQ varying from 40 to 79, poor visual–motor integration and attention deficits (Trauner et al., 1989, Bellugi et al., 1990, Chapman et al., 1996, Gosch and Pankau, 1996, Withers, 1996, Mervis et al., 2001, van der Geest et al., 2004, van der Geest et al., 2005). In contrast to the neuropsychological features listed above, language and musical skills of WS patients are relatively spared, and their personalities are usually friendly, social and engaging (Bellugi et al., 1999). Because of their outgoing character, the mental retardation of WS patients is often underestimated.

The peculiar sets of symptoms and features of WS patients generally result from a 1.55 Mb submicroscopic deletion of 25–30 genes in chromosome band 7q11.23, which is called the WS critical region (Ewart et al., 1993, Francke, 1999, Osborne, 1999, Korenberg et al., 2000). However, some patients suffer from a smaller deletion comprising only a subset of the general spectrum of WS genes. Genotype–phenotype correlation studies of these patients have revealed important new insights in the genetic causes of some of the typical WS symptoms. So far, the strongest correlations have been found for some of the facial symptoms and medical complications. For example, heterozygous deletions of GTF2IRD1 and Elastin have been found to cause the craniofacial abnormalities and vasculopathology, respectively (Ewart et al., 1993, Ewart et al., 1994, Tassabehji et al., 2005). Studies on the genotypical and phenotypical relations have also provided new insights in the genes that may contribute to the neuropsychological characteristics of WS patients, but due to the complexities of the brain and behavior these correlations often are harder to pinpoint to single genes and single symptoms. As it stands hemizygosity of GTF2I probably contributes to the cognitive, behavioral or neurological symptoms of WS (Hirota et al., 2003, Morris et al., 2003), while hemizygous deletions of STX1A or FZD9 (formerly known as FZD3) do not (Botta et al., 1999, Tassabehji et al., 1999). The possible contribution of several other genes that are prominently expressed in the brain awaits further confirmation; these include the roles of LIMK1 (Frangiskakis et al., 1996, Tassabehji et al., 1999, Morris et al., 2003), GTF2IRD1 (Bayarsaihan et al., 2002, Hirota et al., 2003) and cytoplasmic linker protein II (CYLN2) encoding CLIP-115 (De Zeeuw et al., 1997, Hoogenraad et al., 2002). The potential contribution of these genes to the WS phenotype remains to be elucidated, because either conflicting data have been reported and/or we are still missing detailed behavioral examinations of WS patients with particular restricted lesions in the telomeric region.

Here we address the question as to what extent the genes CYLN2 and GTF2IRD1 may contribute to the cognitive and motoric deficits in WS. We describe a new patient in which STX1A and LIMK1 are hemizygously deleted, while CYLN2 and GTF2IRD1 are preserved. Furthermore, we investigated the brain morphology and behavior of two strains of mutant mice in which the expression of CYLN2 (Hoogenraad et al., 2002) and GTF2IRD1 (Durkin et al., 2001) are specifically affected. Since hippocampal and cerebellar structures are likely to be affected in WS patients (Hoogenraad et al., 2002, Jones et al., 2002, van der Geest et al., 2004), we focused our behavioral assessments on potential deficits associated with these brain regions.

Section snippets

Patient

Our patient (WS75) is a boy of 16.8 years of age. His parents gave their written informed consent for the genetic analysis and the behavioral tests. The results of these tests were compared to a group of typical WS patients and healthy controls, who participated in a large study on Williams Syndrome in The Netherlands. The study was approved by the Medical Committee of the Erasmus MC and the VU University Medical Center.

FISH analysis

Chromosome analysis was performed on the blood using standard resolution

Clinical description

Subject WS75 is the first child of non-consanguineous parents of Turkish origin. Pregnancy and delivery were uncomplicated. Psychomotor development appeared normal. The boy started to walk without support and spoke his first words at 1 year of age. After receiving extra Dutch lessons the boy is now attending regular schooling. His intelligence is slightly below normal (full scale IQ 85). Because of the detection of a supravalvular aortic stenosis and multiple peripheral pulmonary arterial

Discussion

In this paper we describe a subject with an atypical deletion in the Williams Syndrome critical region, but without any of the common features of Williams Syndrome except for the congenital heart malformation. Genetic analysis showed that subject WS75 had a deletion of genes FKBP6, FZD9, TBL2, STX1A, ELN and LIMK but not of the genes RFC2, CYLN2, GTF2IRD1 and GTF2I. The results of the tests performed in this patient and the results of the tests in the mutant mice strongly suggest a role for

Acknowledgments

The authors are grateful to the boy and his parents for their cooperation to the study. We would like to thank the participants (and their parents) in the “Rotterdam/Amsterdam Williams Syndrome Study” and the Dutch “Netwerk Williams Syndroom” for their cooperation. This research was supported by grants from the Netherlands Organization for Scientific Research (NWO; Zon-MW), Neuro-Bsik (Senter), EU (SENSOPAC), Prinses Beatrix Fonds and by the Revolving Fund of the Erasmus MC.

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