GENETICS OF  - THALASSEMIA AMONG UAE NATIONALS

Three Normal Hemoglobins Hb A  2  2 96% Hb A2  2  2 3% Hb F  2  2 1%

Developmental expression of the globin chains embryonic hemoglobins             fetal hemoglobins     HbF  adult hemoglobins      HbA 2     HbA    GG AA  developmental time from embryo to adult the arrangement of the  -like genes and the  -like genes reflects their order of developmental expression

 -Thalassemia

Hb F  2  2 (  4) Hb Barts Hb A2  2  2 Hb A  2  2 (  4 ) Hb H FAILURE OF  -GLOBIN LEADS TO:

 -Thalassemia One of the most common human genetic diseases Distribution: Africa, Mediterranean, Middle East, South Asia Definition: Decreased synthesis of  - globin chain.

Transcription Initiation Transcription Termination ‘CAT ‘TATA’ Box Box Exon 1Exon 2 Exon 3 5’3’ Intron 1 Intron 2 Promoter region Translation Initiation Codon (ATG) Polyadenylation Signal Translation Termination Codon (TAA)

The  -Globin Gene Cluster

 The two  -genes are highly similar with few structural divergences.  Their protein product is identical.  The  2 -globin gene have a dominant expression.

 95% of  -thals are due to the deletion of  -globin gene.  The remainder affect other levels of gene processing:  Abnormal RNA processing.  Abnormal or unstable protein products

Silent Carrier State (  -Thal -2) Very common in Mediterranean, Middle East, Southeast Asia. 30% of African-Americans carry this trait. Diagnosis: DNA studies (hematologic studies are normal).

 -Thalassemia - 1 in Trans Single gene deletion on both chromosomes Very common in our area Patients are microcytic hypochromic Normal hemoglobin electrophoresis No risk of hemoglobin Bart’s hydrops fetalis

 -Thalassemia - 1 in CIS Deletion of both  genes on one chromosome. Common in Southeast Asian, Filipino. Fortunately is not recorded in our area. Diagnosis: Microcytic hypochromic, normal Hb electrophoresis, DNA studies Risk of transmission of Hb Bart’s hydrops fetalis

Deletional Hb H Disease 3  genes are detected (-  /--) Parents has to be -  /  --  This type is common in South Asia and not common in our locality. Fairly severe anemia with hemolysis.

Hb H Disease among UAE Nationals Attending Dubai Thalassemia Centre No. of Pts. = 17

Hb H Disease:  Deletional/Non-deletional 9 cases  PA-1  /-  cases  CS  /-  3.7  Non-deletional 3 cases  PA-1  /  PA-1  3 cases  CS  CS 

‘CAT ‘TATA’ Box Box Exon 1Exon 2 Exon 3 5’3’ Intron 1Intron 2 Promoter region Polyadenylation Signal Polyadenylation I Mutation AATAAA-->AATAAG

Hb Constant Spring (Hb CS) Normal  gene UAA CS  gene CAAUAA Terminator Glu Terminator

Mean Hb Values of Hb H Disease (UAE Nationals-Thalas Centre)

Clinical Presentation of Hb H disease in UAE Patients 8 patients with  PA-1  /-   were discovered on routine family screening and were all asymptomatic, leading a normal active life. The homozygous poly A mutation presents with moderate to severe course and one of the 3 patients was transfusion dependent. The homozygous constant spring patients vary in their presentation from mild to moderate.

 -gene status among UAE Nationals (Cord Blood) R esearch done by: Prof. Salah El-Kalla Erol Baysal Thalassemia and Clinical Genetic Center Department of Health & Medical Services

 418 consecutive cord blood samples were analyzed: 214 (51%) were normal  /  204 (49%) were having  -gene problem

Types of  -gene problem in the affected 204 UAE Newborn  140 (68.6%) Heterozygous for 3.7 Kb deletion (-  3.7 /  )  46 (22.6%) Homozygous for 3.7 Kb deletion (-  3.7 /-     5 (2.5%) Heterozygous for 4.2 Kb deletion (-  4.2 /    Compound heterozygous 3.7 and 4.2 Kb deletion (-  3.7 /-     12 (5.9%) Non-deletional  T  mutation

The 12 non-deletional  - mutations in Cord Blood among UAE Nationals Polyadenylation 2 mutation (AATAAA->AATGAA) Polyadenylation 1 mutation (AATAAA->AATAAG) Constant spring mutation (TAA -->CAA) Five nucleotide deletion (GAGGTGAGG-->GAGG)

CORD BLOOD RESEARCH CONCLUSIONS

418 cord blood samples collected from UAE nationals. 204 (49%) having  -gene defect. 214 (51%) normal  -genes

192 (94%) are of the deletion type 12 (6%) are non-deletion 204 with  -gene Defect

186 (97%) is of the  3.7 kb deletion 6 (3%) is of the  4.2 kb deletion 192 with  -gene Deletion

3 Polyadenylation -1 1 Polyadenylation -2 3 Constant spring 6  -5nt del 12 with Non-deletion Defect

Our findings show that  -thal is a very common genetic disorder in the UAE nationals and that Hb H disease has a mild to moderate presentation. All Hb H cases are non- deletional type