Specialty	Clinical Genetics - MD
Languages	English
	Spanish
Gender	Male
E-mail	george.diaz@mssm.edu
Education and Training	MD, S.U.N.Y., Health Science Center
	Residency, Pediatrics, Mount Sinai Hospital
	Fellowship, Human Genetics, Mount Sinai Hospital

Education and Training	MD, S.U.N.Y., Health Science Center
	Residency, Pediatrics, Mount Sinai Hospital
	Fellowship, Human Genetics, Mount Sinai Hospital
Board Certification	Clinical Genetics - MD

Specialty	Clinical Genetics - MD
Languages	English
	Spanish
Board Certification	Clinical Genetics - MD

Chemokine mutations in WHIM syndrome
WHIM syndrome is a rare immunodeficiency causing hypogammaglobulinemia, neutropenia and predisposition to warts. Affected individuals have been found to carry truncating mutations in the tail domain of the CXCR4 chemokine receptor. The pathogenesis of the disease appears to involve both a neutrophil trafficking defect as well as a defect in lymphocyte function. While the nature of the susceptibility to HPV is poorly understood, additional study should provide insight into the role of the receptor in the host response to infection by HPV, a cause of significant human morbidity. Studies currently underway include the characterization of a mouse model expressing mutant CXCR4 in selected hematopoietic tissues, genetic studies with functional candidate genes in families with the WHIM syndrome phenotype without mutations in CXCR4, and biochemical characterization of the signaling perturbations in disease cells carrying CXCR4 truncations.

Disease Gene Discovery and Translational Genomics
The Diaz laboratory studies the molecular basis of inherited human diseases, particularly single-gene disorders. Methodologies applied within the laboratory include linkage analysis, positional cloning, development of animal models and elucidation of disease pathophysiology through biochemical and cell biological studies. By understanding the underlying pathobiology of these disorders, fundamental insights can be gained into more broadly relevant biological or clinical questions.

Tubulin folding defects in human disease
Mutation of a tubulin-specific chaperone protein, TBCE, has been found to cause autosomal recessive Kenny-Caffey syndrome (KCS), a dwarfing syndrome associated with congenital hypoparathyroidism and mental retardation. A spontaneous mutant of the orthologous mouse gene, Tbce, was identified by other investigators in a murine model of peripheral motor neurodegeneration (pmn), implicating the chaperone in maintenance of the microtubule cytoskeleton in motor axons. Biochemical studies have confirmed that the disease pathophysiology is not caused by loss of tubulin folding function, suggesting a novel role for the protein. Interaction with a microtubule growth regulator, EB1 has been demonstrated, consistent with a role for TBCE in the organization of microtubules. Current work is focused on validating this proposed function and exploring the role of TBCE in maintaining microtubule stability. Defects in microtubule stability in neuronal cells appears to be a potential common pathogenic pathway disturbed in several neurodegenerative disorders, suggesting TBCE and its interactors as potential modifiers.

Tian G, Huang MC, Cowan NJ, Diaz GA, Parvari R. Cryptic out-of frame translational initiation of TBCE rescues tubulin formation in compound heterozygous HRD. Proc Nat Acad Sci USA 2006; 103: 13491-13496.

Diaz GA. CXCR4 mutations in WHIM syndrome: a misguided immune system? [review]. Imm Reviews 2005; 203: 235-243.

Oishi K, Diaz GA, Gelb BD, Barchi M. Male infertility due to germ cell apoptosis in mice lacking the thiamin carrier, Tht1. A new insight into the critical role of thiamin in spermatogenesis. Devel Biol 2004; 266: 299-309.

Hernandez PA, Gorlin RJ, Lukens JN, Diaz GA, Francois F, Klotman ME, Bohinjec J. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nature Genetics 2003; 34: 70-74.

. Mutation of TBCE causes the hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome. Nature Genetics 2002; 32: 448-452.

Snyderman S, Diaz GA, Sansiricq C, Wasserstein M, Kornreich M, Edelmann L. Maple Syrup Urine Disease: Identification and carrier frequency determination of a novel founder mutation in the Ashkenazi Jewish population. Am J Hum Genet 2001; 69: 863-868.

Diaz GA, Gelb BD, Risch N, Nygaard TG, Frisch A, Cohen I, Desnick RJ, Amaral O, Maire I, Poenaru L, Caillaud C, Weizberg M, Mistry P, Sa Miranda C. Gaucher Disease: The origins of the Ashkenazi Jewish N370S and 84GG mutations. Am J Hum Genet 2000; 66: 1821-1832.

Diaz GA, Banikazemi M, Gelb BD, Jalali M, Desnick RJ, Vossough P. Mutations in a new gene encoding a thiamine transporter cause the thiamine-responsive megaloblastic anaemia syndrome. Nature Genetics 1999; 22: 309-312.

Diaz G, Banikazemi M, Oishi K, Desnick R. Mutations in a new gene encoding a thiamine transporter cause thiamine-responsive megaloblastic anaemia syndrome. Nat Genet 1999 Jul; 22(3): 309-12.

Diaz GA, Gelb BD, Khan KS. The autosomal recessive Kenny-Caffey syndrome locus maps to chromosome. Genomics 1998; 54: 13-18.