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  Our laboratory conducts both human genetic and basic science research. We are working to uncover the genes involved in brain development and to better understand how their proteins function.
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  Research Interests

Human Genetic Research Projects >> Basic Science Research Projects

We are interested in the fundamental mechanisms directing human brain development. Genetic mutations (changes in an individual's DNA) can alter specific steps of brain development and lead to abnormal brain structure or function due to atypical cell growth, accumulation of cells in abnormal locations in the brain and/or defects in cell function. A brain MRI helps us to see and confirm the structural abnormalities and can guide us to a better understanding of the site of action and the function of the gene(s) involved. By studying individuals affected with these conditions and identifying the associated genes and their mutations, we can learn about the proteins that are important for brain development. We hope that this will lead to better options for diagnosis, management and treatment for affected individuals and their families.

STRUCTURAL DISORDERS OF THE HUMAN BRAIN



Double Cortex Syndrome
refers to a condition that is caused by mutations in the DCX gene and has an X-linked pattern of inheritance. Affected males have classic lissencephaly and affected females can have subcortical band heterotopia (also called double cortex). The DCX gene was uncovered by work done in our lab and we continue to study its function and families affected by this condition.

DCX-Related Disorders GENEReviews

Focal Cortical Dysplasia describes an isolated region of the brain where the neurons did not develop properly. The dysplasia can vary from affecting a small area to the entire right or left side of the brain, a condition called hemimegalencephaly. Sometimes the area of dysplasia is removed during epilepsy surgery. We are interested in comparing the genes in the abnormal brain tissue to the genes in the blood of an affected individual to better understand how this condition occurs. Recently, we found an AKT3 gene mutation in abnormal brain tissue of an individual with hemimegalencephaly.

Heterotopia are nodules or clumps of misplaced neurons that did not move to the correct location in the brain during early development. Periventricular heterotopia (PH), also called periventricular nodular heterotopia (PVNH), are the most common and are seen along the surface of the ventricles in the brain. FLNA and ARFGEF2 are genes known to be associated with periventricular heterotopia. Subcortical heterotopia (SH) and subcortical band heterotopia (SBH) are less common. We continue to study families affected by various types of heterotopia and to look for other causative genes.

X-Linked Periventricualr Heterotopia GENEReviews

Interhemispheric Cyst and Agenesis of the Corpus Callosum have been reported together for many years and their co-occurence is believed to be a genetic condition. We are interested in studying families affected by this condition in an effort to uncover the responsible gene(s).

Lissencephaly is a condition in which the surface of the brain is very smooth and the cerebral cortex is abnormally thick. It is a feature of a number of genetic syndromes and some causative genes have been identified. These include lissencephaly with cerebellar hypoplasia (associated with the RELN gene), Isolated Lissencephaly Sequence (LIS1 gene), Double Cortex syndrome (DCX gene), and Walker-Warburg syndromes. We are interested in studying families affected by lissencephaly in an effort to uncover other responsible genes.

LIS-1 Associated Lissencephaly/Subcortical Band Heterotopia GENEReviews
NINDS Lissencephaly information page

Microcephaly is a condition in which the brain is much smaller than expected for an individual's age. It can be due to many genetic and non-genetic factors and can be isolated or seen along with other abnormalities of the brain or other organ systems. We are primarily interested in studying families with microcephaly alone or in combination with other malformations of the brain and when it is suspected to be genetic. Several genes have been found by our lab to be associated with microcephaly, including ASPM, TRAPPC9, PNKP, WDR62, and ZNF335, and studies are ongoing to better understand them. We continue to study families affected by microcephaly to look for other causative genes.

Primary Autosomal Recessive Microcephaly GENEReviews
NINDS Microcephaly information page

Polymicrogyria (PMG)
describes having too many small gyri (folds) in the brain and can be seen in a variety of patterns affecting different regions of the brain. The affected cerebral cortex often appears thick and so can be confused with pachygyria, where the folds are thick and broad. Polymicrogyria can be isolated or seen with other abnormalities of the brain or other organ systems. Both genetic and non-genetic causes are known. We continue to study GPR56, a gene associated with bilateral frontoparietal polymicrogyria, as well as families affected by many types of polymicrogyria in an effort to uncover other responsible genes.

Polymicrogyria Overview GENEReviews

Schizencephaly describes a cleft, or slit, in the brain that extends from the surface down to the ventricle. Clefts can be on one or both sides of the brain and can be associated with other abnormalities of the brain, such as polymicrogyria. One gene, EMX2, was thought to be associated with schizencephaly but is not a likely cause for most cases. Our lab continues to look for genetic factors in familial schizencephaly by studying families with multiple affected individuals.

NINDS Schizencephaly information page

Walker-Warburg Syndrome (WWS) is a type of congenital muscular dystrophy (CMD) that features a spectrum of abnormalities involving the brain, eyes and muscle. Lissencephaly and cerebellar malformations are the most common brain abnormalities seen in Walker-Warburg syndrome. Several genes have been associated with this condition, including POMT1 and 2, POMGnT1, FKTN, FKRP, LARGE, GTDC2, and others. Our lab continues to study families affected by Walker-Warburg syndrome in an effort to uncover other responsible genes.

Cerebellar Hypoplasia
is a condition in which the cerebellum has not developed completely in size and/or in structure. Cerebellar hypoplasia is common to many disorders, such as Joubert syndrome, which was described by our lab to be associated with the AHI1 gene. Recently, we found the CHMP1A gene to cause cerebellar hypoplasia and microcephaly and continue to study other similar conditions.

NINDS Cerbellar Hypoplasia information page

FUNCTIONAL DISORDERS OF THE HUMAN BRAIN



Autism
describes a group of disorders, together called autism spectrum disorders (ASD), that involve problems with language, communication and social relationships, as well as repetitive behaviors or a narrow range of interests. It is well established that there are genetic factors contributing to the occurrence of autism and in some families these are readily identifiable, such as chromosome abnormalities and Fragile X syndrome. However, most cases are not explained by these conditions and so identifying and understanding other genetic factors is a focus of many research groups. Our lab is focused on studying families with multiple affected individuals in an effort to uncover other responsible genes and mechanisms.

Autism Spectrum Disorders GENEReviews
NIMH Autism Spectrum Disorders Publication
Autism Research at Children's Hospital Boston
My Child Has Autism, Children's Hospital Boston

Epilepsy
is a condition in which nerve cells in the brain sometimes send electrical signals abnormally and cause unusual sensations, behaviors, spasms, seizures or loss of consciousness. It can have many causes and can be associated with other disorders or abnormalities. The genetic causes of some types of epilepsy conditions are known. Our lab is interested in studying epilepsy that occurs along with a structural brain disorder or when it occurs in multiple family members and is not explained by a known genetic condition.

NINDS Epilepsy information page

Intellectual Disability
, previously referred to as mental retardation, can be caused by any condition that alters the development of the brain. It can have genetic and non-genetic causes and be associated with other disorders or abnormalities. Numerous genes have been indentified to be associated with intellectual disability, such as PAK3 and SOBP, which were described with the support of research in our lab. We are interested in studying intellectual disability that occurs along with a structural brain disorder or when it occurs in multiple family members and is not explained by a known genetic condition.

Intellectual Disability, Centers for Disease Control and Prevention
 
 
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