Developmental genetics and birth defects Developmental anomalies certainly

Developmental genetics and birth defects

Developmental anomalies certainly have a major impact on public health. more than 20% of infant deaths were attributed to birth defects. Birth defects are abnormalities (often referred to as anomalies), which are present at birth, in the development of organs or other structures.

Dysmorphology is the study of congenital birth defects that alter the shape or form of one or more parts of the body of a newborn child. The research goals are to understand the contribution of both abnormal genes and nongenetic, environmental influences to birth defects. (Developmental biology)

The clinical objectives are to diagnose a child with a birth defect, to suggest further diagnostic evaluations, to give prognostic information about the range of outcomes that could be expected, to develop a plan to manage the expected complications, to provide the family with an understanding of the causation of the malformation, and to give recurrence risks to the parents and other relatives.

Developmental biology is concerned with a single question: How can a single cell transform itself into a mature animal? In humans, this transformation occurs each time a single fertilized egg develops into a human being with more than 1013 to 1014 cells, several hundred recognizably distinct cell types, and dozens of tissues. This process must occur in a reliable and predictable pattern and time frame. Developmental biology is the scientific field which relates to the study of the process involved in embryogenesis.

Basic developmental processes The effects of developmental genes are mediated through a number of fundamental cellular process During development, cells divide (proliferate), acquire novel functions or structures (differentiate), move within the embryo (migrate), and undergo programmed cell death (often through apoptosis). These four basic cellular processes act in various combinations and in different ways to allow growth and morphogenesis.

• Morphogenesis is accomplished in the developing organism by a number of mechanisms, such as • differential growth, • differentiation, • regulated apoptosis, and • cell migration.

• Development results from the action of genes interacting with cellular and environmental cues. • Information about the genetic factors that initiate, maintain, and direct embryogenesis is incomplete. • The gene families identified in vertebrates usually show strong sequence homology with developmental regulatory genes in Drosophila.

The gene products involved include transcriptional regulators which control RNA transcription from the DNA template, diffusible factors that interact with cells and direct them toward specific developmental pathways, the receptors for such factors, structural proteins, intracellular signaling molecules, and many others. It is therefore not surprising that most of the numerous developmental disorders that occur in humans are caused by genome, chromosome, or gene mutations.

Fundamental mechanisms operating in development • Gene regulation by transcription factors • Cell-cell signaling by direct contact and by morphogens • Induction of cell shape and polarity • Cell movement • Programmed cell death

Gene regulation by transcription factors • Transcription factors control development by controlling the expression of other genes. • Groups of transcription factors that function together are referred to as transcriptional regulatory modules. • Some transcription factors activate target genes and others repress them. Still other transcription factors have both activator and repressor functions.

Homeobox (HOX) gene family The homeobox (HOX) gene system, first described in the fruit fly Drosophila melanogaster. In humans this consists of a total 39 genes organized into 4 cluster on chromosome 7 (HOXA), 17 (HOXB), 12 (HOXC) and 2 (HOXD)

HOX gene family The HOX genes encode transcription factors, which regulate a cascading activity of downstream genes in various developmental pathways involved morphogenesis.

HOX gene family These gene clusters, which have been highly conserved during evolution, show sequential expression. The HOXA and HOXB clusters are specifically involved the establishing the rostral-caudal axis, HOXA and HOXD clusters are important in limb development.

Mutations in HOXA 13 cause a rare condition known as the hand-foot-genital syndrome. This shows autosomal dominant inheritance and is characterized by shortening of the first and fifth digits, with hypospadias in males and bicornuate uterus in females.

• Mutations in HOXD 13 result in an equally rare limb developmental abnormality known as synpolydactyly. • This also shows autosomal dominant inheritance and is characterized by insertion of an additional digit between the third and fourth fingers and the fourth and fifth toes, which are webbed. • Most HOX mutations are so devastating that the embryo cannot survive

Paired-box (PAX) gene family In humans PAX gene family comprise a total number of 9 genes which encode transcription factors involved early embryogenesis, specifically in the determination of cell fate. This was first identified Drosophila that, when mutated, cause defects in body patterning and segmentation. In contrast HOX genes are not arranged in clusters.

Loss-of-function mutations in 5 PAX genes have been shown to cause specific abnormalities consistent with embryonic expression pattern oh the each relevant genes. Gene Locus Expression pattern Abnormality PAX 2 10 q 24 Brain, eye, ear, kidney Renal-coloboma Syndrome PAX 3 2 q 35 Brain, neural tube, neural crest Waardenburg Syndrome PAX 6 11 p 13 Brain, neural tube, eye, pituitary PAX 8 2 q 12 Neural tube, thyroid Congenital hypothyroidism PAX 9 14 q 12 Teeth, ribs and vertebra Hypodontia Aniridia

Waardenburg Syndrome • Waardenburg syndrome type 1 is caused by mutations in PAX 3. • It shows autosomal dominant inheritance and is characterized by sensorineural hearing loss, areas of depigmentation in hair and skin, abnormal patterns of pigmentation in the iris, and widely spaced inner canthi

• Mutations in PAX 6 lead to absence of the iris, which is known as aniridia • This is a key feature of the WAGR syndrome which results from a contiguous gene deletion involving the PAX 6 locus on chromosome 11.

SRY-type HMG box (SOX) genes SRY (Sex determinig Region on Y-chromosome) is the Y-linked gene that plays a major role in male sex determination. A series of genes known as SOX show homology with SRY by sharing a 79 amino acid domain known as the HMG (high mobility group) box. HMG domain activates transcription by DNA which encode for important structural proteins.

In humans it has been shown that mutations in SOX 9 gene cause campomelic dysplasia. SOX 9 is expressed in developing embryo in skeletal primordial tissue, where it regulates type II collagen expression, as well as in the genital ridges and early gonads. SOX 9 is now thought to be one of the several genes that are expressed downstream of SRY in the process of male sex determination.

The sonic hedgehog-patched pathways The Sonic hedgehog gene (SHH) is as well known for its quirky name as for its function. Sonic hedgehog (SHH) gene induces cell proliferation in a tissue specific distribution an is expressed in the notochord, the brain, and the zone of polarizing activity of developing limbs.

After cleavage and modification by the addition of a cholesterol moiety the SHH protein binds with its receptor, Patched (Ptch), a transmembrane protein. The normal action of Ptch is to inhibit another transmembrane protein called Smoothhened, but when bound by Shh this inhibition is released and a signaling cascade within the cell is activated.

Molecular defects in any part of this pathway lead to a number of apparently diverse malformation syndromes; Holoprosencephaly Smith-Lemli-Opitz Syndrome Gorlin Syndrome Grieg cephalosyndactyly Syndrome Pallister-Hall Syndrome Rubinstein-Taybi Syndrome

Holoprosencephaly Mutations in, or deletions of, SHH (chromosome 7 q 36) cause holoprosencephaly in which the primary defect is incomplete cleavage of the developing brain into separate hemispheres and ventricles

Holoprosencephaly The most severe form of this malformation is cyclopia—the presence of a single central eye.

Smith-Lemli Opitz Syndrome Rubinstein-Taybi Syndrome Grieg cephalosyndactyly Syndrome

Cell signaling • One of the hallmarks of developmental processes is cell communication. This communication occurs through cell signaling mechanisms. • Signal transduction is the process whereby extracellular growth factors regulate cell division and differentiation by a complex pathway of genetically determined intermediate steps. • Mutations in many of the genes involved in signal transduction play a role in causing cancer • In some cases they can also cause developmental abnormalities.

RET Proto-oncogene • The proto-oncogene RET on chromosome 10 q 11. 2 encodes a cell-surface tyrosine kinase. • Gain-of-function mutations, whether inherited or acquired, are found in a high proportion of thyroid cancers. • Loss-of-function mutations have been identified in approximately 50% of familial cases of Hirschsprung disease, in which there is failure of migration of ganglionic cells to the submucosal and myenteric plexuses of the large bowel.

• These cell-cell communication systems are commonly composed of a cell surface receptor and the molecule, called a ligand, that binds to it. • On ligand binding, receptors transmit their signals through intracellular signaling pathways. • One of the common ligand-receptor pairs are the fibroblast growth factors and their receptors (FGFR).

FGF Receptors • FGFs play key roles in embryogenesis, including cell division, migration, and differentiation. • The transduction of extracellular FGF signals is mediated by a family of four transmembrane tyrosine kinase receptors.

• There are 23 recognized members of the fibroblast growth factor gene family in the human, and many of them are important in development. • The fibroblast growth factors serve as ligands for tyrosine kinase receptors.

Abnormalities in fibroblast growth factor receptors cause diseases such as achondroplasia

• certain syndromes that involve abnormalities of craniofacial development, referred to as craniosynostoses because they demonstrate premature fusion of cranial sutures in the skull. Apert Syndrome

Programmed cell death • Programmed cell death is a critical function in development and is necessary for the morphological development of many structures. • It occurs wherever tissues need to be remodeled during morphogenesis, as during the separation of the individual digits, in perforation of the anal and choanal membranes, or in the establishment of communication between the uterus and vagina.

Programmed cell death • One major form of programmed cell death is apoptosis. • It is also suspected that defects of apoptosis underlie some other forms of human congenital heart disease such as conotruncal heart defects of Di. George syndrome caused by deletion of the TBX gene located in chromosome 22 q 11. • Apoptosis also occurs during development of the immune system to eliminate lymphocyte lineages that react to self, thereby preventing autoimmune disease

Di. George Syndrome • Microdeletion Syndrome • conotruncal anomalies (tertrology of fallot), • hypoplasia or agenesis of the thymus and parathyroid gland resulting in frequent infections and hypocalcemia, • hypoplasia of the auricle and external auditory canal, • cleft palate, short stature, e

T-box (TBX) genes • T-box gene plays an important role in specification of the paraxial mesoderm and notochord differentiation. • This gene, which is also known as Brachyury, encodes a transcription factor that contains both activator and repressor domains. It shows homology with a series of genes through the shared possession of the T domain, which is also referred to as the T-box.

Loss-of-function mutations in TBX 3 cause the ulnar-mammary syndrome in which ulnar ray developmental abnormalities in the upper limbs are associated with hypoplasia of the mammary glands.

• Loss-of-function mutations in TBX 5 cause the Holt-Oram syndrome. • This autosomal dominant disorder is characterized by congenital heart abnormalities, most notably atrial septal defects, and upper limb radial ray reduction defects that can vary from mild hypoplasia (sometimes duplication) of the thumbs to almost complete absence of the forearms.