Brain Migration Disorder and T-Cell Activation Deficiency Associated with Abnormal Signaling through TCR/CD3 Complex and Hyperactivity of Fyn Tyrosine Kinase[*]

In this study we report on a patient affected by a brain migration disorder and a T-cell activation deficiency presumably inherited as an autosomal recessive trait.

The immunological evaluation revealed that the mitogen stimulation failed to induce a proper up-regulation of membrane expression of T-cell activation markers, and cell proliferation. This functional impairment was associated with abnormalities of the signal transduction process that follows T-cell receptor stimulation. A constitutive hyperphosphorylation of the Fyn tyrosine kinase was documented.

This is the first report on a T-cell signaling abnormality associated with a developmental brain disorder. Whether the alteration of Fyn, which plays a role in both neurological and immunological systems, is responsible for either disorder remains to be elucidated.

Brain migration disorder - T-cell immunodeficiency - Signal transduction - Fyn tyrosine kinase

References

• 1 Arnaiz-Villena A, Timon M, Gallego C R, Blas M P, Correl A, Villa J MM. et al . Human T-cell activation deficiencies.  Immunol Today. 1992;  13 259-265
• 2 Boussiotis V A, Barber D L, Lee B J, Gribben J G, Freeman G J, Nadler M L. Differential association of protein tyrosine kinase with the T cell receptor is linked to the induction of anergy and its prevention by B7 family-mediated costimulation.  J Exp Med. 1996;  184 365-376
• 3 Byrd S E, Osborn R E, Bothan T P, Naidich T P. The CT and MR evaluation of migrational disorders of the brain. Part I. Lissencephaly and pachygyria.  Pediatr Radiol. 1989;  19 151-156
• 4 Chan A C, Kadlecek T A, Elder M E, Filipovich A H, Kuo W L, Iwashima M. et al . ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency.  Science. 1994;  264 1599-1601
• 5 Cooke M P, Perlmutter R M. Expression of a novel form of the fyn proto-oncogene in hematopoietic cells.  New Biol. 1989;  1 66-74
• 6 Dobyns W B. Developmental aspects of lissencephaly and the lissencephaly syndromes. Gilbert EF and Opitz JM Genetic Aspects of Developmental Pathology. New York; Liss, A. R. Inc 1987: 225-241
• 7 Krawinkel M B, Ernst M, Feller A, Flad H D, Mueller-Ermelink H K, Ulmer A J. et al . Lissencephaly, abnormal lymph nodes, and T-cell deficiency in one patient.  Am J Med Genet. 1989;  33 436-443
• 8 Macchi P, Villa A, Giliani S, Sacco M G, Frattini A, Porta F. et al . Mutation of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID).  Nature. 1995;  377 65-68
• 9 Matsumoto N, Pilz D T, Ledbetter D H. Genomic structure, chromosomal mapping, and expression pattern of human DCAMKL1 (KIAA0369), a homologue of DCX (XLIS).  Genomics. 1999;  56 179-183
• 10 Noguchi M, Yi H, Rosenblatt H M, Filipovich A H, Adelstein S, Modi W S. et al . Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans.  Cell. 1993;  73 147-157
• 11 Perlmutter R M. Molecular dissection of lymphocyte signal transduction pathways.  Pediatr Res. 1993;  33 9-15
• 12 Pilz D T, Matsumoto N, Minnerath S, Mills P, Gleeson J G, Allen K M. et al . LIS1 and XLIS (DCX) mutations cause most classical lyssencephaly, but different pattern of malformation.  Hum Mol Genet. 1998;  7 2029-2037
• 13 Scotese I, Gaetaniello L, Matarese G, Lecora M, Racioppi L, Pignata C. T-cell activation deficiency associated with an aberrant pattern of protein tyrosine phosphorylation following CD3 perturbation in Down's syndrome.  Pediatr Res. 1998;  44 252-258
• 14 Sei Y, Whitesell L, Kustova Y, Paul I A, Morse H C, Skolnick P. et al . Altered brain fyn kinase in a murine acquired immunodeficiency syndrome.  FASEB J. 1996;  10 339-344
• 15 Stiehm E R. New and old immunodeficiencies.  Ped Res. 1993;  33 2-8
• 16 Yagi T, Shigetani Y, Furuta Y, Nada S, Okado N, Ikawa Y. et al . Fyn expression during early neurogenesis in mouse embryos.  Oncogene. 1994;  9 2433-2440

1 Financial support: This work was supported by “Progetto MURST-PRIN” (Research Program of National Relevance) 1999, and by Biomed 2 # CT98-3007.