Dr Andrew H Crosby

Research interests

Overview

Neurological disease

The main focus of this group is the identification of genes and subsequent exploration of pathogenic mechanisms responsible for neurological disease, with a particular focus on neurodegenerative diseases of the motor neuron. Over the last four to five years we have mapped the genes responsible for eight neurological conditions (as well as refined the genetic locus of a ninth) and identified the genes for five of these. We also have a strong interest in inherited epilepsy syndromes. Some of the disease genes identified by this group include:

• infantile seizures/GM3 deficiency; SIAT9 (Nat. Genet.36{11}:1225-9, 2004)
• motor neuropathy; SPG17/dHMNV/CMT (Nat Genet. 36{3}:271-6, 2004)
• spastic paraplegia; SPG20 (Nat Genet. 31{4}:347-8, 2002).
• spastic paraplegia with dementia; SPG21 (Am. J. Hum Genet. 73{6}:1147-56, 2003)
• Motor neuropathy (manuscript in preparation, 2007)

Cardiovascular disease

In collaboration with others as well as our own independent studies have also led to the discovery of genes responsible for various forms of cardiovascular disease;

• right ventricular cardiomyopathy; plakoglobin (Lancet 17;355{9221}:2119-24, 2000)
• Noonan syndrome; PTPN11 (Nat Genet. Dec;29{4}:465-8, 2001)
• an autosomal recessive form of hypertropic cardiomyopathy (2007, in preparation)
• bovine model of hypertrophic cardiomyopathy (2007, in preparation)

Inherited birth defects

Other recent projects have also led to the mapping and identification of important developmental molecules associated with inherited birth defects, including:

• A lethal form of bone dysplasia (2007, in preparation)
• Anencephaly (study ongoing)
• Inherited kidney malformation syndrome (study ongoing)
• Omani seizure syndrome-GM3-like syndrome (study ongoing)

Following the identification of these disease genes these projects have progressed towards an elucidation of the function of the mutated molecule using a range of functional technologies.

Consanguinity studies; ‘Windows of Hope’ and ‘FAMguard’

Much of the gene mapping and cloning work described above has stemmed from the identification of diseases which occur at high frequency in the Amish population in Ohio, USA, as part of an ongoing clinical and genetic project. This study, termed ‘Windows of Hope’, follows on from Victor McKusick’s pioneering work in the 1960’s in which he identified a number of diseases within this population. In collaboration with Dr Harold Cross (University of Arizona) the current project expands on these studies with the intention of identifying the responsible genes and elucidating pathogenic processes. The study is now in its 7^th year and in collaboration with numerous clinical and non clinical workers has led to the identification of a number of genes including SPG20 (‘Troyer’ syndrome), SPG21 (‘Mast’ syndrome), GM3 deficiency syndrome (infantile seizure syndrome) and an aggressive form of cardiomyopathy affecting children.

In collaboration with Prof Sandy Raeburn in Oman, The FAMguard project mirrors the Windows of Hope programme. Although still within its first year this project has already led to the mapping of four disease genes, two of which are novel.

Members of the team

Dr Heema Patel

Dr Kamini Kalidas

Dr Michael Simpson

Dr Rachelle Cook

Miss Johanna Reed

Miss Maria Tsaousidou

Miss Katherine Dick

Related Website

www.spasticmodels.org

Selected Publications

Disease gene mapping, identification and mutation studies

Infantile onset symptomatic epilepsy syndrome caused by homozygous loss of function mutations in GM3 synthase (2004). MA Simpson, H Cross, C Proukakis, DA Priestman, DC Neville, G Reinkensmeier, M Wiznitzer, K Gurtz, A Verganelaki, A Pryde, MA Patton, RA Dwek, TD Butters, FM. Platt, AH Crosby. Nat. Genet. Nov;36(11):1225-9

Missense mutations in the BSCL2 gene cause distal hereditary motor neuronopathy type V as well as Silver syndrome (2004). Christian Windpassinger, Michaela Auer-Grumbach, Joy Irobi, Heema Patel, Erwin Petek, Anita Legenstein, Roland Malli, Ines Dierick, Tom Warner, Christos Proukakis, Peter Van Den Bergh, Christine Verellen, Lionel Van Maldergem, L. Merlini, Peter De Jonghe, Vincent Timmerman, Andrew H. Crosby & Klaus Wagner. Nat Genet. 36(3):271-6

Maspardin is mutated in Mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. (2003). Simpson MA, Cross H, Proukakis C, Pryde A, Patton MA, Hershberger R, Crosby AH. Am. J. Hum Genet. 73(6):1147-56.

A Novel Mutation in Desmoplakin Causes Arrhythmogenic Left Ventricular Cardiomyopathy (2005). Norman MW, Simpson M, Mogensen J, Shaw A, Hughes A, Sen-Chowdhry S, Rowland e, Crosby A, and McKenna WJ. Circulation. 2;112(5):636-42.

Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. (2001) Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD.. Nat Genet. Dec;29(4):465-8.

A deletion in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy with non epidermolytic palmoplantar keratoderma and woolly hair (Naxos disease). (2000). Mckoy, G, Protonotarious, N, Crosby, A, Tsatsopoulou, A, Anastsakis, A, Coonar, A, Toutouzas, P, Norman, M, Baboonian, C, Jeffery, S, Mckenna, WJ. Lancet, 355, 2119-2124.

A new locus for autosomal recessive complicated hereditary spastic paraplegia (SPG26) maps to chromosome 12p11.1-12q14 (2004). PA Wilkinson, M Simpson, L Bastaki, H Patel, J Reed, E Samilchuk, R Khan, TT Warner AH Crosby. J. Med Genet;36(11):1225-9.

Selected Clinical Studies

Troyer syndrome revisited: A clinical and radiological study of a complicated hereditary spastic paraplegia. (2004). Proukakis, C, Cross, H, Patel, H, Patton, MA, Valentine, A, Crosby, AH. J. Neurol;251(9):1105-10.

A clinical, genetic and biochemical study of SPG7 mutations in hereditary spastic paraplegia. (2004). Philip A Wilkinson, Andrew H Crosby, Christopher Turner, Lloyd J Bradley, Lionel Ginsberg, Nicholas W Wood, Anthony H Schapira, Thomas T Warner. Brain. 127(Pt 5):973-80

A clinical, genetic and candidate gene study of Silver Syndrome, a complicated form of hereditary spastic paraplegia. (2004). Thomas T. Warner, Heema Patel, Christos Proukakis¹, Johanna A. Reed, Laura McKie, Adrian Wills, Michael A. Patton, Andrew H. Crosby. J Neurol. 251(9):1068-74.

A clinical and genetic study of SPG5A linked autosomal recessive hereditary spastic paraplegia. (2003). Wilkinson PA, Crosby AH, Turner C, Patel H, Wood NW, Schapira AH, Warner TT. Neurology. 2003 Jul 22;61(2):235-8.

Paternal Germline Origin and Sex-Ratio Distortion in Transmission of PTPN11 Mutations in Noonan Syndrome. (2004) Tartaglia M, Cordeddu V, Chang H, Shaw A,Kalidas K, Crosby A, Patton MA, Sorcini M, van der Burgt I, Jeffery S, and Gelb BD. Am. J Hum Genet. 75 (3): 492-497.

PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. (2002). Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner HG, Bertola DR, Crosby A, Ion A, Kucherlapati RS, Jeffery S, Patton MA, Gelb BD. Am J Hum Genet. 2002 Jun;70(6):1555-63.

SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. (2002) Patel H, Cross H, Proukakis C, Hershberger R, Bork P, Ciccarelli FD, Patton MA, McKusick VA, Crosby AH. Nat Genet. 2002 Aug;31(4):347-8.

The Silver syndrome variant of hereditary spastic paraplegia maps to 11q12-14, with evidence for genetic heterogeneity within this subtype. (2001). Patel, H, Hart, PE, Warner, T, Jeffery, S, Patton, MA, Crosby, AH. Am J Hum Genet. 69(1):209-15.

A large family with hereditary spastic paraparesis due to a frame shift mutation of the spastin (SPG4) gene: association with multiple sclerosis in two affected siblings and epilepsy in other affected family members. (2001) Mead SH, Proukakis C, Wood N, Crosby AH, Plant GT, Warner TT. J Neurol Neurosurg Psychiatry. Dec;71(6):788-91.

Invited Editorials and Other Studies

Endogenous spartin, mutated in a form of hereditary spastic paraplegia, has a complex subcellular localisation suggesting diverse roles in neurons. (2006) Robay D, Patel H, Simpson MA, Brown N, Crosby AH. Exp Cell Res. 10;312(15):2764-77.

INVITED EDITORIAL: Disruption of cellular transport: a common cause of neurodegeneration? Crosby, AH. (2003). Lancet Neurol. 2(5):311-6

INVITED EDITORIAL. Is the transportation highway the right road for hereditary spastic paraplegia? (2002). Crosby, AH, Proukakis, C. Am J Hum Genet. 71(5):1009-16.

The identification of a conserved domain in both spartin and spastin, genes mutated in hereditary spastic paraplegia. (2003). Ciccarelli FD, Proukakis C, Patel H, Cross H,Azam S, Patton MA, Bork P and Crosby AH. Genomics. 2003;81(4):437-41.