7. Transcription factors

The transcription factors are the genes whose products will activate or suppress other genes and thus mutations in the transcription factors can lead to a variety of birth defects. These include the Homeobox (HOX) genes, Paired box Genes (PAX), T Box (TBX), SRY type HMG Box (SOX) genes, Zinc Finger Genes. The transcription factors as mentioned above leads to an orderly distribution of already differentiated cells to form specific tissues and organs by spatial arrangement and this process are called pattern formation. Studies in Drosophila the homeotic or HOX genes determine segment identity and faulty expression of these genes result in major structural abnormalities.

Drosophila has eight HOX genes arranged in single cluster whereas in humans there are 39 HOX genes arranged in four homeobox cluster genes on chromosomes 7p, 17q, 12q, 7q as HOX A, HOX B, HOX C, HOX D respectively numbered as 1–13. These genes regulate the cell fate and thus establish a pattern along the cephalocaudal axis and also limb bud axis and genital axis. Thus these genes play important role in development of CNS, axial skeletons, limbs gastrointestinal and urogenital systems.

The Hox genes are numbered and always expressed in cephalocaudal manner and there is a direct linear relation between the position of a particular gene and its spatial expression so playing a major role in early morphogenesis. Thus it results in a coordinated patterning of the derivatives of all the three germ layers. There are 39 HOX genes in humans but it is very astonishing that very few syndromes and malformation is attributed to HOX gene mutations. This can be explained by assuming that mutation in HOX genes can be so devastating that the embryo cannot survive. There can also be another explanation that the paralogous group of HoX genes like HOXA4, HOXB4, HOXC4 and HOXD4 though situated in different chromosome segments can compensate for loss of function or mutation in paralogous genes.

The notch delta pathway is responsible for the somite formation and it is expressed in oscillating pattern. The Notch accumulates in that paraxial mesoderm which is destined to form the

The Sonic Hedgehog -Patched Gli pathway promotes cell proliferation in the notochord, floor plate of neural tube, brain and developing limbs and gut. This Sonic Hedgehog Gli pathway malfunctioning can lead to a variety of birth defects and cancers which includes holoprosencephaly to a basal cell carcinoma, medulloblastoma, etc. The Sonic Hedgehog is first broken down to form an active N-terminal form to which a cholesterol moiety gets added which binds

The normal action of Patched is to inhibit a transmembrane protein Smoothened but Sonic Hedgehog-Patch combination the inhibition is released. Smoothened thus activated. Further activates a cascade within the cell involving the GLI family of transcription factors, i.e., activation of GLI 1 and GLI 2 and Inhibition of GLI 3. Disruption of hedgehog signaling during development either due to mutation or teratogens can lead to developmental anomalies. Excessive activation of Hedgehog pathway does promote increase in angiogenic factors and

Sonic Hedgehog functioning is essential for human development and its absence or mal expression is associated with certain specific defects as holoprosencephaly, limb defects and ventral defects of neural tube. This sonic hedgehog which is a morphogen and its signaling is dependent on its concentration and duration. The fundamental cellular processes like proliferation, survival, cell fate determination, migration, apoptosis during development are controlled by key developmental signaling pathways like Receptor tyrosine Kinase, Hedgehog,

The transcription factors are the genes whose products will activate or suppress other genes and thus mutations in the transcription factors can lead to a variety of birth defects. These include the Homeobox (HOX) genes, Paired box Genes (PAX), T Box (TBX), SRY type HMG Box (SOX) genes, Zinc Finger Genes. The transcription factors as mentioned above leads to an orderly distribution of already differentiated cells to form specific tissues and organs by spatial arrangement and this process are called pattern formation. Studies in Drosophila the homeotic or HOX genes determine segment identity and faulty expression of these genes result in major structural abnormalities.

Drosophila has eight HOX genes arranged in single cluster whereas in humans there are 39 HOX genes arranged in four homeobox cluster genes on chromosomes 7p, 17q, 12q, 7q as HOX A, HOX B, HOX C, HOX D respectively numbered as 1–13. These genes regulate the cell fate and thus establish a pattern along the cephalocaudal axis and also limb bud axis and genital axis. Thus these genes play important role in development of CNS, axial skeletons, limbs

lead to development of cancers of brain, lungs, mammary gland, prostate and skin [5].

somite and then once the somite is formed it reduces in concentration [1].

to the Patched 1 and Patched 2 trans membrane proteins in the target cells.

BMP, WNT, Notch, Retinoic acid signaling pathways [4].

7. Transcription factors

82 Genetic Diversity and Disease Susceptibility

gastrointestinal and urogenital systems.

The paired box genes (PAX-genes) are a highly conserved DNA sequence and 9 PAX genes have been identified in humans. Loss of function of 5 PAX genes has been associated with developmental abnormalities in humans. PAX2 mutations causes renal coloboma syndrome in which renal malformations occur along with defects in eye. PAX 6 mutations also lead to eye defects as absence of iris. The SRY is a Y linked gene and plays a major role in male sex determination. This SRY genes show homology with the SOX genes and in humans it is seen that mutations in SOX2 have shown to cause anopthalmia or micropthalmia, esophageal atresia, and genital hypoplasia in males.

The T-box genes or TBX genes are dispersed throughout the human genome. Loss of function or mutation of TBX3 causes ulnar-mammary syndrome, which includes developmental abnormality of upper limb and mammary gland hypoplasia. Mutations in TBX-5 cause Holt Oram syndrome, which is an autosomal dominant disorder, characterized by congenital heart abnormalities and upper limb abnormalities.

The zinc finger genes are the genes, which have a zinc finger motif, and it acts as a transcription factor, which binds to DNA, and thus they can result in single gene developmental disorders. GLI3 is a zinc finger motif containing gene and large deletion or translocations involving GLI3 results in Grieg cephalopolydactyly and on the other hand frame shift mutation of the same gene result in Pallister-Hall syndrome which is characterized with polydactyl imperforate anus hypothalamic hamartomata. Mutations in WT1 another zinc finger motif gene causes Wilms tumor. Mutations in other zinc finger genes such as ZIC2 and ZIC3 results in holoprosencephaly and lateral polarity defects, which are essential for development of leftright axis.

The testis determining factor or the SRY gene, which is now determined to be located in the sex-determining region of the Y chromosome and evidence, shows that this is the primary factor, which determines maleness. Expression of SRY gene leads to activation of other genes like SOX9 which leads to the differentiation of the medulla of the undifferentiated gonad to develop into a testis in which the Leydig cells are formed which starts producing testosterone which leads to Wolffian duct stimulation and formation of male external genitalia.

The Sertoli cells on the contrary start producing the Mullerian Inhibitory hormone, which regresses the Mullerian duct. On the absence of SRY gene the medulla of the undifferentiated gonads develop into ovary the Mullerian duct forms the internal genitalia and the external genitalia does not fuse and develop into normal female genitals. Normal sexual differentiation is completed by 14 weeks though the testis descends at a much later part of pregnancy [1].
