February 25, 2015
Williams Syndrome:The Extraordinary Profile of a Micro-deletion
Alexus Edmonds ’13 graduated from Lake Forest College with a bachelor’s degree in Neuroscience. During her time at Lak...
Alexus Edmonds
Department of Neuroscience
Lake Forest College
Lake Forest, Illinois 60045
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*This author wrote the paper as a part of BIOL346: Molecular Neuroscience under the direction of Dr. DebBurman.
Abstract
Williams Syndrome (WS) is a rare genetic disorder caused by variable hemizygous micro-deletions on chromosome 7. Depending on the exact genes deleted WS results in distinct cognitive, behavioral, and physical phenotypic profiles. Our lab characterized various deficits and gifts of WS. Deficits include hypersociability, poor visual-spatial skills, inferior cognitive abilities, and supravalvar aortic stenosis (SVAS). Gifts include musical proficiency, preserved linguistic abilities, and face recognition. Neuroanatomically, others and we have identified decreased brain size, preserved cerebellar volume, decreased cerebral midline length, larger corpus callosum bend, reduced occipital lobes, and superior longitudinal fasciculus (SLF) abnormalities linked to visual-spatial and other deficits. Other colleagues have mapped key hemizygous genes to distinct phenotypes; the five best-characterized genes are Elastin, LIMK1, CLIP2, GTF2I, and GTF2IRD1. ELN is important for proper vascular development; hemizygous deletion is linked to SVAS. LIMK1 and CLIP2 work together in neuronal morphology and neurogenesis by regulating actin and microtubule dynamics, respectively. Hemizygous deletions in LIMK1 and CLIP2 affect proper neuronal development and synapse formation. Deficits in GTF2I produce hypersensitivity and anxiety, while lack of GTF2IRD1 causes craniofacial deficits. Despite such major advances in WS, for the future, many other hemizygous genes will need similar characterization, increasing the possibility for effective molecular-based treatments for WS.
Introduction
Human variations grant scientists the opportunity to expand what is known about human biology. The rare genetic disorder Williams Syndrome (WS) in particular is providing groundbreaking expansions in the scientific field1. Williams Syndrome was first discovered in 1952 by Fanconi and Williams2. WS occurs in approximately 1 in 20,000 births2 and is caused by variable hemizygous micro-deletions on chromosome 72. Five of the best characterized hemizygous gene deletions include Elastin, LIMK1Kinase, CLIP2, GTF2I, and GTF2IRD12. Variations of these micro-deletions result in distinct cognitive, behavioral, and physical phenotypic profiles; all of which attribute to the extraordinary profile of WS3; this is exemplified in figure 1.
Individuals with WS have very distinct physical phenotypes such as SVAS a potentially fatal heart defect, hypercalcemia, and spine curvature3. WS individuals also have rather unusual facial features, characterized as “elfin” or “pixie- like”, full lips, high cheekbones, broad forehead, wide mouth, flat nasal bridges, upturned noses, and almond shaped eyes3. Other WS characteristics include poor spatial coordination and hypersociablity1,4 and severe cognitive impairment with IQ scores ranging from 50 to 702,4. WS is also characterized by remarkable gifts such as, profound linguistic abilities, face recognition, and musical proficiency.
Currently there is no treatment for WS; patients must be treated for their symptoms throughout their lives5. Due to this renewed attention has been given to WS by both our lab and the labs of fellow geneticists and cognitive psychologists5. Our interest in WS ascended from the uneven cognitive profile of the syndrome as well as the limited information known about the disorder6. For almost two decades our lab and collaborating labs have worked to create a complete neuroarchitectural profile of WS3.Our labs seeks to fill all gaps of WS, ultimately linking the cognitive, behavioral, and physical phenotypic profiles of WS.
Fig 1: Healthy Chromosome Compared to WS Chromosome: The arrows from the five key genes ELN, LIMK1, CLIP2, GTF2I, and GTF2IRD1 on a healthy chromosome indicate their proper functions. The arrows from the five key genes ELN, LIMK1, CLIP2, GTF2I, and GTF2IRD1 on a WS chromosome indicate their hemizygous functions, resulting in various deficits2.
Neurocognitive Profile
Our lab used previous knowledge about the relationship between neurobiological systems and cognitive functions to develop our experimental framework3. Our method was to match cognitive abnormalities with specific neurobiological causes3; allowing us to map neurocognitive abnormalities with distinctive phenotypic features, highlighting both the strengths and weakness of WS3,6. All subjects in our studies were recruited through family contacts, Williams Syndrome Association, national and regional conferences, private physicians, geneticists, cardiologists, and others lab3.
We administered a general IQ test to act as our foundation for a neurocognitive profile of WS3. WS individuals displayed severe cognitive impairment across and array of general cognitive tasks, placing them in the mild-to-moderate mentally retarded range7. Global standard scores ranged from 40-90 with a mean of approximately 55; this range indicates individual variations within the WS population7. Depending on the severity of cognitive incompetence some WS adults are able to live independently or semi-independently, while others require a great deal of help3. Out of all cognitive tasks, mathematics was the area of greatest difficulty within the WS population. The general IQ test also demonstrated a delay in conceptual knowledge, as well as deficits in spatial-cognition.
Deficits in Spatial Cognition
WS individuals are characteristically described as having severe spatial cognition deficits8. We assessed spatial cognition using the Block Design subset of the Wechsler Intelligence Scale for Children-Revised (WISC-R), which required subjects to arrange a set of blocks to replicate increasingly complex stimulus patterns2. WS subjects received extremely low global scores compared to local scores2 suggesting difficulty with the overall configuration of stimulus patterns and strength in local aspects of the pattern2. These spatial difficulties are also depicted in pen and paper tasks. When asked to copy a Navon- styles hierarchical local/global figure, WS patients are able to identify the local image but not the global image, for example when shown a large letter “D” composed of lower case “Y’s,” they only identify the “Y’s”2; this is displayed in figure 2.
Facial Recognition: Hey I know you!
Apart from visuo-spatial deficits, WS individuals have a remarkable ability to recognize faces9; recognizing almost any face, discriminating and remembering familiar and unfamiliar faces alike9. WS individuals are able to recognize faces in various lighting and dimensions9. The Benton Test of Facial Recognition is a face-discrimination task which we used to assess facial recognition strengths within WS subjects9. The Benton test shows the same face under different conditions and assesses the WS subject’s ability to identify the face as familiar or unfamiliar9. Other test such as the Warrington Recognition Memory Test and the Mooney Closure task assessed unfamiliar face recognition and facial closure abilities9. In these studies WS subjects performed incredibly well in each task compared to DS subjects and normal controls, emphasizing the facial recognition proficiency of WS individuals9.
Elaborate Language
Another cognitive ability that is spared within the WS population is linguistic abilities10. We compared WS linguistic abilities disorders such as Down syndrome (DS) and Autism10. Our results showed WS individuals have the most elaborate and preserved verbal skills compared to both DS and Autism10. WS adolescents and adults are extremely articulate and talkative10. Linguistic skills serves as a characterized gift among WS individuals, however early development does not depict this11. During the initial stages of life, WS individuals speak their first words between 20-30 months old similar to DS individuals, displaying strong grammatical skills later in development11. Our lab collected data using the MacArthur Communicative Development Inventory (CDI), a parental report, to measure language development on two scales, Words and Gestures Scale and Words and Sentences Scales; assessing developing communication and grammatical skills in both WS and DS11. Data revealed that at the point of grammatical acquisition WS individuals show rapid and significant improvement compared to DS individuals; these reports indicate a linguistic phenotype divergence between the two groups11. Our lab also assessed grammatical skills using syntax testing3; during these test WS subjects were asked to detect and correct glitches in the arrangement of a sentence. Results indicated WS subjects scored significantly higher than DS subjects in syntax testing, further indicating the linguistic divergence between the two disorders3.
Further results indicate rather complex conversational language among WS individuals; WS individuals typically produce an array of complex language within their everyday diction12. WS individuals’ diction is so complex at times that it often times is categorized unusual12. WS individual tend to use very sophisticated wording in inappropriate context, for example in one of our studies a subject said, “I have to evacuate the glass” instead of simply saying empty the glass3. WS individuals use their language abilities to engage others socially7. Oddly enough WS individuals’ sociability acts more as a deficit than a gift4.
Dangers of Hypersociability
Our lab assessed WS hypersociability using the parent questionnaire, the Salk Institute Sociability Questionnaire (SISQ)1. Parents reported that their WS children appear unable to resist approaching strangers, hence placing themselves in great danger4. These reports support the results of our previous study, which indicated WS individuals are unable to differentiate approachability based on facial expressions and rely on superficial signals as positive cues of approachability13. Another study showed that hypersociability occurs as early as infancy in WS individuals13. During a parental separation task, WS infants less frequently showed negative facial expression, and when a stranger (assessor) entered the room the infant became instantly intrigued and approached the stranger in a fearless manner. Infants were particularly interested in the face of the stranger13.
This unusual social phenotype drew the attention of our lab as well as other labs1. Quantifiable measures were used to assess the unrestrained social behavior in efforts of understanding the usual social phenotype (Jones et al., 2000). Sociability was first measured in association with linguistic expression based on affect and language through storytelling and interviews1. WS and DS subjects were asked to create a story based on a cartooned photograph; the extravagant wording style of WS subjects vividly depicted the expressive and engaging nature of WS subjects1. WS subjects not only use very expressive language but also modified their voices to match with certain expressions, as well as “audience hookers” such as guess what happens next?, to further engage their listeners1. We have encountered WS children who have stated there is no such thing as strangers, and act as everyone in the world is their friend1. An example of this overt friendliness was seen in a study assessing social expression through a biological interview tasks1. Subjects were asked to describe themselves, family, friends, and activities that interested them1. During the interviews after answering a question WS subjects asked the interviewers the same question, seeking information from them1. WS cognitive deficits and gifts led our lab to the brain morphology of WS individuals. We hypothesized brain morphology acted as the foundation blocks of these behaviors1,3.
Neuroanatomical Profile
Gross Anatomical Observation
We began by conducting a series of gross anatomical observations on fours autopsy specimens, of individuals who had been diagnosed with WS at some point in their lives14. Overall MRI images indicate that an overall reduction of gray matters (GM) and white matter (WM) volumes, along with disproportionate decreases in thalamus and occipital lobe sizes15. WS brains are also relatively low in weight, weighing approximately 800- 1000g14. MRI images conducted on living WS patients also revealed low brain weight, with a total volume decrease of 13% in brain volume compared to normal controls16; with cerebral volumes showing a 13% decrease compared to a 7% cerebellar volume decrease, representing a preservation of cerebellar volume16. Various studies have shown that both the right and left cerebral hemispheres of WS bend significantly less17. Revealing curtailed shape from the top to the bottom, particularly within the posterior cerebral portion of the hemispheres18. Observations also indicated the central sulcus appears shortened compare to normal control in the central sulcus continues until reaching the midline14,15. These observations led us to create cortical thickness maps, to depict a full image of the WS brain15.
Cortical Complexity & Integrity
We define cortical complexity as the amount of gyrification (folding) within the WS brain15. Our study revealed increased cortical thickness within a large neuroanatomical region encompassing the perisylvian language-related cortex15. This region surrounds that posterior portion of the Sylvian fissures and extends to the lateral fissure, and is linked to verbal and musical abilities in WS15. We also observed cortical thickness along the inferior surface of the right temporal lobe into the collateral and entorhinal cortex15. This area also included the well persevered fusiform face area which is linked to face recognition proficiency in WS15,19. We also looked into the white matter integrity and fiber tracking of two major WM pathways20 the superior longitudinal fasciculus (SLF); known as the “where” pathway associated with the dorsal stream and the inferior longitudinal fasciculus (ILF); known as the “what” pathway associated with ventral stream20. Results indicated the ILF pathway was less affected in WS compared to the SLF, particularly the right SLF which had significantly higher integrity and fiber tracking than ILF20. These abnormalities suggest that the right SLF plays a key role in abnormal visuo-spatial construction20 given the right lateralization of visuo-spatial construction functions along the dorsal stream20. Once we had successfully created a cortical complexity and integrity map, our lab attempted to link the highlighted brain areas with specific WS gifts and deficits.
Brain Morphology and Behavior
The WS brain follows a topographic pattern, suggesting a neuroanatomical basis for some of the disorder’s neurobehavioral features17. For example the amygdala in the WS brain is significantly reduced in volume compared to normal controls14,16; we predict amygdala dysfunction is linked to the WS deficit of abnormal social behavior but is also partially responsible for the gift of face recognition, and musical proficiency14,16. The dorsal portion of the amygdala’s lateral nucleus (LNd) appears to be largely reduced in the WS brain seems to be partially responsible for visual –spatial deficits14 due to the fact being that lateral nucleus connections ascend from the visual association cortex14. MRI images also revealed an enlarged cerebellar vermis in WS, which we believe is linked to hyper-sociality and heightened affective expression.
We and our colleagues also observed many corpus callosum abnormalities in the WS brain (Luders et al., 2007). Such as, shorter corpus callouses, less curvature, smaller midline lengths, and thinner regions along the posterior surface compared normal controls21. We attribute these morphological alterations to the unique cognitive and behavioral profiles of WS individuals17,21. Our lab also performed numerous studies attempting to map visual-spatial deficits with specific brain areas22. We attribute decreased total brain volumes and occipital gray volumes to the deficits within the visual spatial system of WS22. Most recently our labs linked insular volume reduction particularly in the right hemisphere23 to the development of social-emotional processing and severe phobias23. After gathering significant data about the relationship between brain morphology and behavior, we turned our attention to genetic associations.
Genetic Profile
WS behavior and morphology cannot be fully understood without investigating the molecule genetics of the disorder. Currently our lab is seeking the assistance of our colleagues, for further knowledge about the molecular genetics of WS24. The contributions of our colleagues presents information about five of the best characterized hemizygous genes deleted on chromosome 724; Elastin, LIMK1Kinase, CLIP2, GTF2I, and GTF2IRD124. Each of these hemizygous gene micro-deletions lead to distinct cognitive, behavioral, and physical phenotypic profiles all of which attribute to the extraordinary profile of WS.
Elastin’s Impact on the Heart
Elastin (Eln) protein allows blood vessels and connective tissues to remain flexible and elastic25. WS individual have a hemizygous deletion of the elastin gene which leads to sever cardiac disorder such as supravalvular aortic stenosis (SVAS)25; SVAS causes narrowing of the aorta and pulmonary arteries and is linked to hypertension and even death25,26. A study conducted in a colleagues’ lab revealed loss-of-function mutation in one elastin gene caused inherited arterial disease and SVAS27. Another study by this same lab also revealed elastin deficiency leads to increased cellularity; specifically smooth muscle cell proliferation, and lumen narrowing27. Mouse models also depict the importance of elastin during embryonic and postnatal development27,28. In hemizygous Eln mice (Eln +/-) at embryonic day 18 cardiac morphology is similar to wild type mice, it is not until birth that morphological differences are seen28. At birth the Eln +/- mouse has significantly increased left ventricle (LV) pressure and reduced compliance; ability to yield to pressure without elastic disruption28. Further studies also revealed early Eln deficiency can lead to extreme arterial diameter decrease, thinner lamellae, shorter distance between lamellae, and increased fragmentation within the lamellae29. Comparatively, postnatal mice models revealed Eln (+/-) mice have decreased aortic diameters by postnatal day 725 and significantly high systolic blood pressure by postnatal day 1425. Our colleagues are also exploring the development adaptation of Eln +/- mice in efforts of creating possible therapeutic treatments30. Angiotensin II receptor blockers (ARBs) used to treat high blood pressure and heart failure were administered to Eln +/- mice and dramatically decreased blood pressure30. These results indicate there are possible treatments for hemizygous Eln deletion; however, constant treatment is required.
LIMK1 & CLIP2: Neuronal Development
Other colleagues are looking into the connections between LIMK1 and CLIP231. LIMK1 and CLIP2 work together in neuronal morphology and neurogenesis respectively regulating actin and microtubule dynamics31. LIMK1 is critical for proper development of the central nervous system32 and is indirectly activated by Rac; a small GTPase of the Rho family which mediates stimulus induced actin cytoskeletal organization33. Together the two mediate the phosphorylation of ADF/cofilin in the brain32,33. ADF/cofilin are key regulators of actin cytoskeleton dynamics, which have been implicated in growth cone motility and neurite extension34. LIMK1 not only promotes and stabilizes cofilin expression32 but it also co-precipitates with neuregulin in regulating synaptic formation and maintenance35. The absence of LIMK1 leads to abnormalities in synaptic structures, spine development, and cytoskeletal functioning34. Conversely CLIP2 regulates microtubule dynamics36 and is expressed in various areas of the central nervous system such as the amygdala, hippocampus, and cerebellum36. Normal CLIP2 has an amino terminal head with two microtubule-binding (MTB) motifs and are surrounded by serine rich-regions and long coiled-coil regions36. Mutated CLIP2, however, lack efficient MTBs and cause profound bundling in microtubule networks at the distal ends of microtubules36. CLIP2 mutations are suggested to contribute to the altered neurodevelopment in WS due to altered microtubule dynamics36. Hemizygous deletions in both LIMK1 and CLIP2 are suggested to have a combined effect on cytoskeletal deficits seen in WS36 such as growth deficiency and motor coordination deficits linked to CLIP2 mutation and heightened locomotor activity and impaired spatial learning linked to LIMK1 mutations.
GTF2I >2IRD: Phenotypic Resemblance to WS
Additional genetic mapping has been conducted on genes GTF2I and GT2IRD. GTF2I normally helps regulate neurocognitive development37, hemizygous deletion of GTF2I causes neurodevelopmental deficits resulting in hypersensitivity, visual-spatial deficits, hypersociability, and anxiety37. GTF2I +/- mice models showed significantly increase maternal separation- induced anxiety compared to wild type mice37 anxiety levels were measured by ultrasound vocalization37. Another study showed GTF2I +/- mice have increased social interaction with unfamiliar mice38. Both of these results resemble specific WS phenotypes of hypersociability and anxiety37,38. The gene GTF2IRD however is required for proper craniofacial development40. Deficits in GTF2IRD cause abnormalities to facial development, motor functioning, and behavior40. These abnormalities have been seen in various mouse models40 with images depicting excess tissue in the nose and lips, smaller body sizes, round faces, and short snouts40. These results suggest GTF2IRD is a key contributor of the facial appearance of WS individuals. A novel study reported on the linking effect on GTF2 +/- and GTF2IRD +/-, suggesting the two are associated with visual spatial deficits seen in WS41. This research, however, is not as concrete as the results of previous studies, but does open possibilities for future studies.
Fig 2: Spatial Deficits in WS: A. Block Design subset of the Wechsler Intelligence Scale for Children-Revised (WISC-R), assessing WS subjects ability to arrange a set of blocks to replicate a model figure2. WS subjects are unable to properly construct the model figure, indicating deficits in visual spatial construction2. B. Navon- styles hierarchical local/global task assessing WS subjects ability to recognize local and global figures in a model2. WS subjects recognize the local letter “Y” but are unable to recognize the global letter “D”; suggesting deficits in visuo-spatial cognition.
Conclusion
The research of our lab and the labs of our colleagues has greatly contributed to what is presently known about WS3. Our lab has mainly contributed to creating cognitive and anatomical profiles of WS1,3; characterizing both gifts and deficits of the disorder1,3. Additionally the contributions our colleagues have led to major advances about the underpinning molecular genetic basis of WS24. Nonetheless there is still a large amount of gene characterization that needs to done24. Thus far WS research has yielded many advances in the scientific field amongst an array of disciplines3,24; allowing the phenotypic profile of WS to be logically connected to its anatomical and genotypic profiles3. For example we now know the characteristic visual spatial deficits seen in WS are attributed to decreased cerebral volumes22 as well as LIMK131, GTF2 and GTF2IRD deficits41. Such descriptive mapping would not have been possible in past years.
Unfortunately there is still no cure for WS treatments are still only being given to reduce symptoms and not to treat WS as a whole12. Hence requiring research into other specific genes within the deletion area of chromosome 714. By continuing research we and our colleague are in fact increasing the possibility of effective molecular- bases treatments and therapies14,24.Presently the work of our colleagues has led to innovative diagnostic tools allowing for infancy diagnosis based on genetic and metabolic markers12. Prior to genetic diagnosis, many WS individual were left undiagnosed until mid-adolescence or even adulthood12. Early diagnosis may actually expose more WS cases then previously reported12.
Without the collaborative assistance and diligence of our colleagues, WS would only be cognitively and anatomically mapped12. For that reason we sincerely appreciate the works of our colleagues. As we all know WS is a genetically based disorder; without extensive research into its molecular underpinnings several aspects of the disorder will remain unclear12. Therefore it is essential that our lab and the labs of our colleagues continue to work diligently in solving the medical mysteries of WS. At this time our colleagues and we plan to continue WS research in efforts to answer unsolved questions about the disorder14. We hypothesize that our future research as well as our previous research hopefully will give insight into potential treatments and therapies3. Also we believe that with the knowledge already known about WS and the knowledge that will be obtained in future studies, finding a cure for WS is more than probable14.
Acknowledgements
I would like to thank Dr. Shubhik DebBurman for his support throughout the process in both gathering and interpreting information to write this review. I would also like to thank my Bio 346 classmates for their encouragement and support throughout this entire semester.
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