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NEUROLOGY 2007;69:442-447
© 2007 American Academy of Neurology

Location and type of mutation in the LIS1 gene do not predict phenotypic severity

G. Uyanik, MD, D. J. Morris-Rosendahl, PhD, J. Stiegler, MD, J. Klapecki, MD, C. Gross, MSc, Y. Berman, MD, P. Martin, MD, L. Dey, MD, S. Spranger, MD, G. C. Korenke, MD, I. Schreyer, MD, C. Hertzberg, MD, T. E. Neumann, MD, P. Burkart, MD, C. Spaich, MD, M. Meng, MD, H. Holthausen, MD, L. Adès, MD, J. Seidel, MD, E. Mangold, MD, G. Buyse, MD, PhD, P. Meinecke, MD, U. Schara, MD, C. Zeschnigk, D. Muller, MD, G. Helland, MD, B. Schulze, MD, M. L. Wright, MD, S. Kortge-Jung, MD, A. Hehr, PhD, U. Bogdahn, MD, G. Schuierer, MD, J. Kohlhase, MD, L. Aigner, PhD, G. Wolff, MD, U. Hehr, MD and J. Winkler, MD

From the Department of Neurology (G.U., J.S., U.B., L.A., J.W.), University of Regensburg, Center for Human Genetics (C.G., A.H., U.H.), and Institute of Neuroradiology (G.S.), Bezirksklinikum Regensburg, Regensburg, Institute for Human Genetics and Anthropology (D.J.M.-R., L.D., C.Z., J.K., G.W.), Albert Ludwigs University Freiburg, and Department of Neuropediatrics (M.M.), St. Josefs Hospital, Freiburg, Epilepsy Center Kehl-Kork (P.M.), Kehl, private practice (Human Genetics) (S.S.), Bremen, Department of Neuropediatrics (G.C.K.), Center for Pediatrics, Oldenburg Hospital, Institute of Human Genetics and Anthropology (I.S.), University of Jena, Department of Child Neurology (C.H.), Vivantes Clinic Neukoelln, Berlin, Institute of Human Genetics (T.E.N.), University of Muenster, Department of Neuropediatrics (P.B.), Caritas Hospital, Bad Mergentheim, Institute of Human Genetics (C.S.), Olga Hospital Stuttgart, Neuropediatric Clinic and Clinic for Neurorehabilitation/Epilepsy Center for Children and Adolescents (H.H.), Vogtareuth, SRH Clinic for Pediatrics Gera (J.S.), University of Jena, Gera, Institute of Human Genetics (E.M.), University of Bonn, Clinical Genetics (P.M.), Altona Children's Hospital, Hamburg, Department of Neuropediatrics (U.S.), City Hospital Neuss, Institute of Medical Genetics (D.M.), Klinikum Chemnitz, private practice (Human Genetics) (B.S.), Hannover, Children's Hospital Park Schonfeld (M.L.W.), Kassel, and Institute of Prenatal Medicine and Genetics (S.K.-J.), Dusseldorf, Germany; Department of Medical Genetics (J.K.), Institute of Mother and Child, Warsaw, Poland; Department of Clinical Genetics (Y.B., L.A.), Children's Hospital at Westmead, Sydney, Australia; Department of Child Neurology (G.B.), University Hospitals of K.U. Leuven, Belgium; and Department of Pediatrics (G.H.), Levanger Hospital, Norway.

Address correspondence and reprint requests to Dr. J. Winkler, Department of Neurology, University of Regensburg, Universitaetsstr. 84, D-93053 Regensburg, Germany juergen.winkler{at}klinik.uni-regensburg.de

Background: Lissencephaly is a neuronal migration disorder leading to absent or reduced gyration and a broadened but poorly organized cortex. The most common form of lissencephaly is isolated, referred as classic or type 1 lissencephaly. Type 1 lissencephaly is mostly associated with a heterozygous deletion of the entire LIS1 gene, whereas intragenic heterozygous LIS1 mutations or hemizygous DCX mutations in males are less common.

Methods: Eighteen unrelated patients with type 1 lissencephaly were clinically and genetically assessed. In addition, patients with subcortical band heterotopia (n = 1) or lissencephaly with cerebellar hypoplasia (n = 2) were included.

Results: Fourteen new and seven previously described LIS1 mutations were identified. We observed nine truncating mutations (nonsense, n = 2; frameshift, n = 7), six splice site mutations, five missense mutations, and one in-frame deletion. Somatic mosaicism was assumed in three patients with partial subcortical band heterotopia in the occipital-parietal lobes or mild pachygyria. We report three mutations in exon 11, including a frameshift which extends the LIS1 protein, leading to type 1 lissencephaly and illustrating the functional importance of the WD domains at the C terminus. Furthermore, we present two patients with novel LIS1 mutations in exon 10 associated with lissencephaly with cerebellar hypoplasia type a.

Conclusion: In contrast to previous reports, our data suggest that neither type nor position of intragenic mutations in the LIS1 gene allows an unambiguous prediction of the phenotypic severity. Furthermore, patients presenting with mild cerebral malformations such as subcortical band heterotopia or cerebellar hypoplasia should be considered for genetic analysis of the LIS1 gene.

*These authors contributed equally to the article.

Supported in part by the "Regensburger Forschungsförderung der Medizinischen Fakultät" (ReForM; University of Regensburg, Germany), the "Fritz-Thyssen Stiftung" (Köln, Germany), and the Joint German-Israeli Research Program of the Federal Ministry of Education and Research (BMBF) and the Ministry of Science and Technology (MOST) "Toward neural stem cell based therapies: the impact of neuronal migration" (BMBF#01GA0510).

Disclosure: The authors report no conflicts of interest.

Supplemental data at www.neurology.org

Received October 27, 2006. Accepted in final form March 2, 2007.


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