"INDEXTOPICS1. Genetics an overview 2. What is Dowling Degos Disease 3. How common is Dowling Degos Disease4. Symptoms 5. What is KRT5 gene? 6. How mutation causes Dowling Degos Disease 7. Diagnosis8. Similar diseases to Dowling Degos Disease 9. Treatment10. Necessity of genetic testing 11. Where can the testing be done? 1 GENETICS- AN OVERVIEWGenetics is the study of heredity, genes and genetic variation in livingorganisms. Gene is a region in DNA which encodes the functional protein.DNA is the genetic material. It is responsible for the formation andfunctioning of the human body. The genetic material is compactly packed ina thread like structure called chromosome. This genetic material is passed onto the offspring (child) from both the parents. Each of the parents contributestowards the constitution of the half of the genetic material of the off spring.The complete genetic material is known as the genome. DNA is a nucleic acid. The whole information in DNA is encoded by A-Adenine,T- Thymine, G- Guanine, C- Cytosine. Whenever the sequence isperfectly aligned the correct information is coded and all the functioning ofthe system goes smooth. A mutation in the sequence may hamper the properfunctioning of the system. A mutation most of the times causes a change inthe actual sequence which inturn leads to the problem in the properfunctioning.CENTRAL DOGMA OF LIFE*http://www.design4evolution.net/ This is the central dogma of life. The process keeps on going and goingthroughout the life. The DNA gets transcribed to form RNA which in turntranslates into a functional protein. Any problem in this process causes aproblem in the functioning of the human system. These problems can be dueto any mutation. During the process of DNA replication, errors sometimesoccur in the chain formation of the second strand. These errors, calledmutations, can have an impact on the physical appearance of an organism,especially if the mutation occurs within that sequence of a gene whichencodes for a protein. Not all mutations are harmful. Some mutations may 2 even undergo unnoticed. But some are extremely deleterious and mayhamper the human body system. A normal healthy human contains 46chromosome or 22 pairs of autosomes and one pair of sex chromosomes.The sex chromosome in female is XX while in males in XY. DID YOU KNOW?1. Wehave more than 98% similarity in our DNA with Chimpanzees.2. We humans share 99.9% of similar DNA with each other.3. There are 3 billion base pairs in our genome.4. We humans are 50% similar to bananas.WHAT IS DOWLING DEGOS DISEASE.WHAT IS DOWLING DEGOS DISEASEDowling Degos disease is a disease which is autosomal dominant in nature,which means that even if one of the parents is affected by the disease theoffspring will be affected by the disease. This disease is basically a skincoloration disorder in which the skin can either become hyper-pigmented(darkening of skin) or hypo-pigmented (lightening of skin) along with othersymptoms. Generally, Dowling Degos Disease is caused by a mutation inKRT5 gene. The disease usually onsets at puberty and is progressive innature. It progresses slowly - slowly and stops after reaching a certain stage.The disease leads to formation of lesions on skin.HOW COMMON IS DOWLING DEGOS DISEASE?.The disease is a rare autosomal disease. Majority of cases have beenreported in China. The disease is familial in nature which means it continuesfrom one generation to another. Few cases have been reported in parts ofsouthern, northern and western parts of India. 3 SYMPTOMS1. Unusual lightening or darkening of the skin colour.2. Appearance of lesions which look like scar on areas like neck, armpits and other regions which have major folds. 3. The lesions may appear like open pores on the skin and appear like pits.The pits are usually 1-3 mm in size.4. The pigmentation slows over years and usually worsens in summers.5. The disease usually has an onset at puberty.6. The pigmentations are symmetrically distributed. WHAT IS THE FUNCTION OF KRT5 GENE?KRT5 belong to family of genes called KRT. The official name of KRT5gene is keratin 5, type II. The other names of the gene are K5, KRT5 or CK5,58 KDa cytokeratin, cytokeratin 5, EBS2, K2C5_HUMAN, Keratin-5,KRT5A, keratin, type II cytoskeletal 5. The gene has been mapped tochromosomal locus 12q13.13. KRT5 gene is responsible for encoding theKeratin 5 protein. Keratin 5 is produced by keratinocytes cells. Keratins arefibrous proteins responsible for constructing the structural frame work ofsome of the cells including skin, hair etc. on the outer surface of theepidermis. Keratin 5 along with Keratin 14 makes the intermediate filaments.These filaments together form strong networks which help adhere thekeratinocytes together and anchor the epidermis to underlying layers of skin.The network of keratin intermediate filaments provides strength to the skinand protects it from any kind of damage caused by friction and othereveryday physical stresses.Intermediate filaments are the building blocks of the cytoskeleton. They arerod shaped in structure and are 8-12nm in diameter. The main function ofintermediate filaments is to create cell cohesion and prevent the acutefracture of epithelial cell sheets under multiple kinds of stress or tensionwhich may exert pressure on the cells. These intermediate filaments have agreat resistance to compression, twisting, stretching and bending forceswhich are provided by the interaction between the various proto-filamentsthus giving it a great amount of toughness and strength. 4 *http://www.mechanobio.info/HOW MUTATION CAUSES DOWLING DEGOS DISEASE?Dowling Degos Disease is caused by the mutation in the KRT5 gene. Themutation is a loss of function mutation. This type of mutation causes the lossof a particular type of function that a gene performs and a result the functionstops or alters thereby leading to a diseased condition. The loss of functionmutation of the KRT5 gene causes haplo-insufficiency of of K5.Haplo-insufficiency is the condition in which only one pair of the generemains functional as a result of which enough of the gene product is notproduced which is normally produced in a healthy condition as a result ofthis disease is caused. This haplo-insufficiency of K5 leads to a singleunpaired k14 which is soluble and thus causes Dowling Degos disease.Dysfunction of the intermediate filament cytoskeleton causes aberrantdistribution of melanosomes degradation suggesting a delayed degradationof melanin granules. This disruption of melanosome transport is thought tocause the pigmentation aberrations seen in individuals with Dowling-Degosdisease. 5 DIAGNOSIS OF DOWLING DEGOS DISEASE.The diagnosis of Dowling Degos disease is predominantly base upon the1. Physical symptoms and attributes of the patients showing pigmentations.2. The histopathological and biopsy analysis. Genetic testing is required to differentiate the various forms of the disease aswell as for differentiating it from the diseases showing similar symptoms andclinical features i.e, for differential diagnosis.DISEASES SIMILAR TO DOWLING DEGOS DISEASE.1. Dyschromatosis Symmetrica HereditariaCombination of hyperpigmented and hypo-pigmented macules on the face,back of the hands, and feet can be seen in this disease. The mutationinvolved is on the gene ADAR1 located on 1q21.3 which causes this form ofthe disease. 2. Dyshcromatosis Universalis HeredetiaraCharacterized by a mixture of hyperpigmented and hypo-pigmentedmacule s distributed randomly over the body the disease is caused by the mutation ofgene ABCB6. The gene is mapped to 6q24.2-q25.2 for DUH1, 12q21-q23for DUH2 and DUH 3 is caused by mutation in ABCB6 gene on 2q35.3. Galli Galli Disease. This disease has characters similar to generalized dowling degos disease butwith the reported distinguishing histological feature of acantholysis i.e., lossof coherence between epidermal cells due to the breakdown of intercellularbridges. The disease is too caused by the mutataion in KRT5 gene. But themutation is a frameshift mutation. 4. Haber's SyndromeIt is characterized by an early onset with eruptions on skins associated withmultiple truncal lesions. The disease is caused by the mutation in KRT5 gene.But it has the physical symptoms different from Dowling Degos disease. 6 5. Reticulate Acropigmentation of Kitamura Hyperpigmented lesions in RAK involve the flexor aspects of the wrists,neck, eyelids and periorbital areas. Other features include pits, breaks in theepidermal ridge pattern and occasionally, plantar thickening of the skin andhair loss. RAK´s onset is usually in childhood. The disease is associated withmutations in ADAM10 gene located on 15q21.3.The Dowling Degos disease in itself is of multiple types. The followingforms are present which can differentiated on the basis of mutations indifferent genes.1. Dowling Degos Disease 1- It is the generalised form of the disease causedby mutation on KRT5 gene located on the chromosome 12q13.3.2. Dowling Degos Disease 2- The second type of Dowling Degos Disease iscaused by the mutation in the POFUT1 gene located at chromosome20q11.21.3. Dowling Degos Disease 3- This form of the disease is mapped tochromosome 17p13.3. 4. Dowling Degos Disease 4- The fourth form of the disease is caused due tomutation in the POGLUT1 gene on 3q13.33.TREATMENT OF THE DOWLING DEGOS DISEASE AND ITSASSOCIATED DISEASES.The treatment of Dowling Degos disease has not been completely found. Butsome laser treatments have been known to show some relief to the patients.Generalized Dowling Degos disease can be treated with the Er:YAG laserpulse energy between 1,000 and 1,200 mJ, three consecutive passes, DUHpatients have shown improvement after treatment with narrowbandultraviolet B (NBUVB) therapy, while the DSH patients have been treatedwith 1-mm miniature punch grafting in combination with 308-nm excimerlight. 7 WHY IS GENETIC TESTING NECCESSARY?The disease is an autosomal dominant skin pigmentation disorder. Asmentioned earlier that there are multiple forms of the disease and many otherdiseases which share clinical features similar to generalized Dowling Degosdisease, thus there differentiation on the basis of genetic analysis isnecessary. Physical symptoms may or may not help in identifying the correctform of the disease, therefore a differentiation on the genetic basis will helpin finding the actual gene involved in the disease and the type of mutationhas occurred. A mis-diagnosis can be fatal and may lead to a wrong line oftreatment. Therefore, surety about the exact disease form is a must and thus,genetic testing is a necessity. WHERE CAN YOU GET THE TEST DONE?If you have any symptoms of any of the above diseases then you can agenetic testing done for the disease at Institute of Genomics andIntegrative Biology, Mathura Road, New Delhi by giving your bloodsamples. The correct gene involved for the disease will be identified bydoing the genetic analysis from the blood sample so that the correcttreatment could be followed.8 "