Molecular Genetics

Luba Kalaydjieva's team is involved in research into the molecular basis of neuropsychiatric disorders.

For more than a decade, this work has focused on a specific population, the Roma/Gypsies, whose history of migrations, geographic dispersal, social segregation, as well as traditional endogamy, have shaped up a unique genetic profile that facilitates the discovery of disease genes. We have been successful in the identification of novel genes and mutations which, although initially found in a specific population, are of general relevance and help doctors and scientists alike to understand the causes and mechanisms of wide-spread disorders affecting the global population.

The other important avenue of our research is schizophrenia, a major psychiatric disorder, with a devastating effect on sufferers and their families. Schizophrenia has been a focus of genetic research for many years, however the complexity of the human brain and the inherent heterogeneity of psychiatric disorders have proved to be a major challenge. Our studies rely on the pioneering work of the UWA Centre for Clinical Research in Neuropsychiatry, where the use of a comprehensive battery of psychological, electrophysiological and brain imaging tests has allowed the dissection of the clinical category of schizophrenia into subtypes that are more proximal to the biological processes involved and thus more amenable to genetic analysis.

Senior Research Staff

Professor Luba Kalaydjieva Head, Molecular Genetics and Australian Schizophrenia Research Bank - WA Laboratory Research: genetics of neurological and psychiatric disorders; founder populations

Dr Bharti Morar Fellow Research: molecular genetics of schizophrenia; population genetics

Research Details

The Roma/Gypsies

The Gypsies are a people of Indian origins, now scattered across most countries of the world. The exodus from India, subsequent migrations and population fissions, as well as the Gypsies' social history of discrimination and persecutions, have translated into a string of demographic bottlenecks, founder effects and limited genetic diversity. Unlike other well-known founder populations with a similar biological history, such as the Ashkenazi Jews, the Gypsies have been ignored by genetic research. We have initiated the first studies and gradually established collaborations with researchers all over the world to investigate genetic disorders, biological history, and population genetics. Aiming at understanding the molecular basis of the most common Mendelian disorders in this population, we have investigated their molecular basis (i.e. the genes and mutations involved) and epidemiology, thus providing the tools for accurate diagnosis and prevention at the level of the affected individual, the family, and the community. Furthermore, the homogeneous molecular basis of Mendelian disorders in the Gypsy population has allowed us to study genotype-phenotype correlations and examine the full spectrum of clinical manifestations in individuals sharing the same ancestral mutation.

Our current research, in collaboration with Australian and international colleagues, is focused on the genetics of epilepsy in the Gypsy population. Epilepsy is one of the most common neurological disorders and a leading cause of disability worldwide. While generally a treatable condition, around 30% of epilepsy cases are resistant to treatment. Both the genetics and the mechanisms of the disease are complex and we hope that our studies of large affected Gypsy families may contribute new knowledge to the field. The characteristics of the Gypsies as a genetically isolated founder population lead to the expectation that the same molecular defects will be shared across families, thus facilitating gene identification and the analysis of clinical variability.

Schizophrenia

This research is conducted in collaboration with the UWA Centre for Clinical Research in Neuropsychiatry, the Laboratory for Genetic Epidemiology at WAIMR, and the Australian Schizophrenia Research Bank. Our efforts aim at the identification of genetic variants conferring susceptibility to schizophrenia. Since a well-defined phenotype is the main prerequisite for productive genetic research, we have focused on a homogeneous and heritable schizophrenia subtype of developmental origin, which is characterized by impaired memory performance and pervasive cognitive deficit (CD). Based on neuropsychological, electrophysiological and neuroimaging data on our CD subtype, we are targeting genes involved in specific relevant brain functions, such as synaptic development and plasticity. We are adopting a systems biology approach that examines networks of interacting proteins and takes into account the modular functional organization of the living cell.

Major Achievements / Highlights

Professor Kalaydjieva's team is the pioneer and world leader in research into the genetics of the Roma/Gypsies. Our population genetic studies have confirmed the linguistic and cultural anthropology hypothesis on the Indian ancestry of the Gypsies, and, surprisingly, have unambiguously demonstrated that the geographically dispersed and culturally and linguistically divergent Gypsy populations of Europe share the same origins and stem from a small group of common ancestors. Our data point to a single exodus from India, around 35-40 generations ago. Consecutive population fissions have occurred after the arrival of the Gypsies in Europe, giving rise to numerous sub-isolates. Genetic drift and founder effects, common to the entire Gypsy population or more recent and confined to individual sub-isolates, and different degrees and sources of admixture, have shaped a peculiar molecular mosaic of maternal and paternal lineages and disease-causing mutations, ancestral and "imported" by admixture.

Our research has led to the identification of the founder mutation and molecular epidemiology of the following hereditary disorders in the Gypsy population:

• Charcot-Marie-Tooth Disease type 4D (Hereditary Motor Sensory Neuropathy-Lom)
• Charcot-Marie-Tooth Disease type 4C
• HMSN - Russe
• Congenital Cataracts Facial Dysmorphism Neuropathy Syndrome
• Infantile GM1 gangliosidosis
• Sphingomyelinase-deficient Niemann-Pick Disease
• Galactokinase deficiency
• Limb-Girdle Muscular Dystrophy type 2C
• Spinal Muscular Atrophy
• Congenital Myasthenia
• Hereditary Inclusion Body Myopathy

Notable Publications

1. Tournev I, Kalaydjieva L, Youl B, Ishpekova B, Guergueltcheva V, Kamenov O, Katzarova M, Kamenov Z, Raicheva-Terzieva M, King RH, Romanski K, Petkov R, Schmarov A, Dimitrova G, Popova N, Uzunova M, Milanov S, Petrova J, Petkov Y, Kolarov G, Aneva L, Radeva O, Thomas PK. 1999. Congenital Cataracts Facial Dysmorphism Neuropathy (CCFDN) syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations. Ann Neurol 45(6):742-750. [NCBI PubMed Entry]
2. Mullner-Eidenbock A, Moser E, Klebermass N, Amon M, Walter MC, Lochmuller H, Gooding R, Kalaydjieva L. 2004. Ocular features of the congenital cataracts facial dysmorphism neuropathy syndrome. Ophthalmology 111(7):1415-23. [NCBI PubMed Entry]
3. Varon R, Gooding R, Steglich C, Marns L, Tang H, Angelicheva D, Yong KK, Ambrugger P, Reinhold A, Morar B, Baas F, Kwa M, Tournev I, Guerguelcheva V, Kremensky I, Lochmuller H, Mullner-Eidenbock A, Merlini L, Neumann L, Burger J, Walter M, Swoboda K, Thomas PK, von Moers A, Risch N, Kalaydjieva L. 2003. Partial deficiency of the C-terminal domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome. Nature Genet 35(2):185-189. [NCBI PubMed Entry]
4. Angelicheva D, Turnev I, Dye D, Chandler D, Thomas PK, Kalaydjieva L. 1999. Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome: a novel developmental disorder in Gypsies maps to 18qter. Eur J Hum Genet 7(5):560-6. [NCBI PubMed Entry]
5. Mastroyianni SD, Garoufi A, Voudris K, Skardoutsou A, Stefanidis CJ, Katsarou E, Gooding R, Kalaydjieva L. 2006. Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome: a rare cause of parainfectious rhabdomyolysis. Eur J Pediatr (in press). [NCBI PubMed Entry]
6. Merlini L, Gooding R, Lochmuller H, Muller-Felber W, Walter MC, Angelicheva D, Talim B, Hallmayer J, Kalaydjieva L. 2002. Genetic identity of Marinesco-Sjogren/myoglobinuria and CCFDN syndromes. Neurology 58(2):231-6. [NCBI PubMed Entry]
7. Mihaylova V, Hantke J, Sinigerska I, Cherninkova S, Raicheva M, Bouwer S, Tincheva R, Khuyomdziev D, Bertranpetit J, Chandler D, Angelicheva D, Kremensky I, Seeman P, Tournev I, Kalaydjieva L. 2007. Highly variable neural involvement in sphingomyelinase-deficient Niemann-Pick disease caused by an ancestral Gypsy mutation. Brain 130(Pt 4):1050-61. [NCBI PubMed Entry]