Over the past few years several different types of Human Skin Disorders have been characterized at clinical and molecular levels. In a number of cases of skin disorders, not only chromosomal localizations but aberrations in the genes involved have been identified. The discovery of the disease genes has revolutionized understanding about better diagnosis and therapeutics of hereditary skin abnormalities. Pakistan, due to its ethnic diversity and social customs, harbor large consanguineous families, which are the major source of traditional methods for mapping disease genes. For the study, presented in my PhD dissertation, I travelled to some of the very remote areas of Pakistan and studied eighteen families with skin disorders. Travelling to some of these areas is one of the most exhaustive and wearisome experience of my life. Non- availability of hospitals, proper transport facilities and even roads in some of the areas has made the experience more remarkable and unforgettable. In the present study, six families with hereditary ectodermal dysplasias (A-F) and twelve families with hereditary hair loss (G-R) have been characterized both at clinical and molecular levels. Affected individuals in each family were thoroughly examined for all kinds of abnormalities especially those affecting skin, hair, nail, teeth and sweat glands. Each family was then characterized at molecular level by testing linkage to the known/unknown genes and DNA sequencing using automated DNA sequencer. In a couple of families, human genome was scanned using more than 500 highly polymorphic microsatellite markers to locate the disease gene. In family A, affected individuals presented features of hypohidrotic ectodermal dysplasia segregating in an autosomal recessive manner. The two affected individuals in the family showed clinical features including fine and sparse scalp hair, absent eyebrows and eyelashes, absent axillary and pubic hair, conical teeth, diminished sweating, dry and thin skin, protruding prominent lips, pointed chin, frontal bossing, hyperpigmentation of the skin around the eyes and mouth, and saddle-shaped nose. Genotyping data established linkage in the family to gene EDAR on chromosome 2q11-q13. Subsequently, sequence analysis of the gene revealed a homozygous splice donor site mutation (c.442+1G>C, IVS5+1G>C) in affected individuals of the family. In family B, fourteen individuals showed typical features of X-linked recessive ichthyosis (RXLI). Analysis of family pedigree and clinical features of the affected individuals led directly to screening of the gene STS, mapped earlier on chromosome Xp22.32. Analysis of the PCR results and DNA sequencing detected a complex double deletion in DNA of the affected individuals. This involved deletion of exons 1-2 and 5-10, and > than 1.2 Kb upstream and downstream DNA sequence of the gene STS. In family C, all three affected individuals exhibited features of lipoid proteinosis including warty skin, diffuse acneiform scars on the skin, infiltration on the face and hands, and yellow erythocytic lesions on the hands. Genotyping results showed linkage of the family to gene ECM1, located on chromosome 1q21. However, sequence analysis failed to identify potential sequence variants in the gene ECM1 in DNA of the affected individuals. Six individuals in two families (D and E), presented characteristic features of a condition of missing fingernails and toenails called anonychia congenita. Linkage in both the families was established to a recently discovered gene RSPO4, mapped on chromosome 20p13. Sequence analysis failed to detect any potential sequence variant in the gene RSPO4 in affected individuals of the family D. However, in the other family (E), sequence analysis revealed a novel nonsense mutation (c.18C>A; p.Cys6X) in the only affected individual. In family F, all three affected individuals showed features representing a novel form of ectodermal dysplasia. Affected individuals exhibited features including sparse scalp hair, sparse eyebrows and eyelashes, sparse beard and moustache in male affected individuals, and dystrophic nails. Skin in the affected individuals was thin and not easily healed on receiving the injury. Hyperhidrosis was observed on palms and soles of the affected members. Human genome scan using more than 500 polymorphic microsatellite markers, established linkage in the family to chromosome 20p13. The highest two-point LOD score, at zero recombination fraction (θ=0.00), of 1.97 was obtained at a marker D20S482. Maximum multi-point LOD score of 2.65 was achieved at three markers (D20S199, D20S113, D20S842) along the disease-interval. Sequencing of two candidate genes (RSPO4, TGM3), located in the linkage interval of 3.88 Mb, in two affected and one unaffected member of the family failed to detect potential sequence variants. Of the twelve families with hereditary hair loss disorders, presented here, the family G showed segregation of woolly hair in autosomal dominant fashion. Affected individuals exhibited short tightly curled twisted hair entangled with each other. Linkage in the family was established to type II keratin gene KRT74 on chromosome 12q12-14.1. Sequence analysis of the gene KRT74 identified a novel splice site mutation (c.IVS8- 1G>A) in all nine affected individuals of the family. In six families (H, I, J, K, L, M), affected individuals presented features of hereditary hypotrichosis. The affected individuals showed absent/sparse/wooly scalp hair, sparse to absent eyebrows and eyelashes, and missing axillary and pubic hair. In family H linkage was established to DSG4 gene on chromosome18q12.1-q12.2, in two families (I, J) to LIPH gene on chromosome 3q27 and three other families (K, L, M) to the gene LPAR6 on chromosome 13q14.11-q23.21. Sequence analysis of the gene DSG4 detected a previously reported deletion mutation (Ex5_8del) in all the affected individuals of the family H. In family I and J, screening of the gene LIPH revealed 2 base pairs homozygous deletion mutation (c.659_660delTA) leading to frameshift and premature termination codon 69 base pairs downstream of the mutation point (p.Ile220ArgfsX25). Screening of the gene LPAR6 detected a previously reported 4-bp insertion mutation (c.69insCATG; p.24insHisfsX52) in affected individuals of families K and L and a missense mutation (c.562A>T; p.Ile188Phe) in affected members of family M. In three families (N, O, P), affected individuals showed typical features of atrichia with papular lesions (APL). All eighteen affected individuals in the three families showed complete absence of scalp hair, eyebrows, eyelashes and other body hair. Linkage in the families was established to gene HR on chromosome 8p21.3. Sequence analysis revealed a novel nonsense mutation (c.2458C>T; p.Arg819X) in exon 11 of the gene in family N. In the other two families (O and P), sequence analysis failed to identify potential sequence variants in the gene HR. In two families (Q and R), a novel form of hair loss was observed. In family Q, affected individuals presented features of late onset of hair loss, which ultimately lead to complete hair loss from all body parts including scalp, eyebrows, eyelashes and pubic. Linkage in the family was tested with several other hair loss genes, but no evidence of linkage was found. In family R, twelve individuals showed late onset of hair loss. In all the affected individuals, loss of hair started from top of the scalp at the age of 25 years, which ultimately led to complete baldness at the age of 30-35 years. Human genome scan using more than 500 microsatellite markers failed to detect linkage in the family on any chromosome. The data obtained from the present study contributed in publishing the following articles 1. Wasif N, Naqvi SK, Basit S, Ali N, Ansar M, Ahmad W (2011) Novel mutations in the keratin-74 (KRT74) gene underlie autosomal dominant woolly hair/hypotrichosis in Pakistani families. Human Genetics 129: 419-424 2. Azeem Z, Wasif N, Basit S, Sohail M, Ahmad W (2011) HR mutations underlies Atrichia with Papular Lesions in four Autosomal Recessive Pakistani Families. 3. Wasif N, Ahmad W (2011) A novel nonsense mutation in RSPO4 gene underlies autosomal recessive congenital anonychia in a Pakistani family. Pediatric Dermatology (In Press) 4. Khan S, Habib R, Mir H, Umm-E-Kalsoom, Naz G, Ayub M, Shafique S, Yamin T, Ali N, Basit S, Wasif N, Kamran-Ul-Hassan Naqvi S, Ali G, Wali A, Ansar M, Ahmad W (2011) Mutations in the LPAR6 and LIPH genes underlie autosomal recessive hypotrichosis/woolly hair in 17 consanguineous families from Pakistan. Clinical and Experimental Dermatology (In Press) 5. Wasif N, Tariq M, Ali G, Hassan MJ, Ahmad W (2010) A novel splice site mutation in the EDAR gene underlies autosomal recessive hypohidrotic ectodermal dysplasia in a Pakistani family. Pediatric Dermatology 27: 106-108 6. Tariq M, Ayub M, Jelani M, Basit S, Naz G, Wasif N, Raza SI, Naveed AK, ullah Khan S, Azeem Z, Yasinzai M, Wali A, Ali G, Chishti MS, Ahmad W (2009) Mutations in the P2RY5 gene underlie autosomal recessive hypotrichosis in 13 Pakistani families. British Journal of Dermatology 160: 1006-1010 7. Jelani M, Wasif N, Ali G, Chishti M, Ahmad W (2008) A novel deletion mutation in LIPH gene causes autosomal recessive hypotrichosis (LAH2). Clinical Genetics 74: 184-188 8. Azeem Z, Jelani M, Naz G, Tariq M, Wasif N, Kamran-Ul-Hassan Naqvi S, Ayub M, Yasinzai M, Amin-Ud-Din M, Wali A, Ali G, Chishti MS, Ahmad W (2008) Novel mutations in G protein-coupled receptor gene (P2RY5) in families with autosomal recessive hypotrichosis (LAH3). Human Genetics 123: 515-519" xml:lang="en_US