Localization of five human genes by clinical and molecular genetic methods

Abstract: Four of the research projects reported in this thesis start from the gene effects observed in clinical practice. Finding a disease causing gene is challenging, exciting and beneficial for the patient, the family and for the society.Larsen syndrome is a congenital malformation syndrome, most often dominantly inherited, and with usually modest symptoms from the large joints, hands, feet and face. Some of the gene-carriers may however be seriously affected. The positive attitude from the members of this multi-generation family from Western Sweden has enabled localization of the responsible gene to chromosomal region 3p21-p14, from which the gene is yet to be cloned (Paper I).Hereditary multiple exostoses is also a dominantly inherited disorder of the bone tissue. All gene carriers exhibit multiple bone tumors on the long bones usually in the proximities of joints. The bony outgrowth from the growth plates may destroy the joint or the adjacent bone structure, but also cause a lot of pain and cause asymmetrical growth in children. Occasionally the exostoses may endanger vital parts of the body. At least 3 human genes may cause exostoses. Affected members from a large pedigree from Western Sweden and their relatives were committed to contribute in the pursuit of the liable gene. The chromosomal locus 11p12-p11 where EXT2 gene resides was first found to be the disease causing in this family. Later a novel EXT2 mutation could be demonstrated in all affected. (Paper II)Best macular dystrophy is a dominantly inherited disorder of the eye. The symptoms from impaired vision start in the tens and progress during adolescence and adulthood, sometimes leading to blindness. Accumulation of lipofuscin pigment in and below retinal pigment cells gradually destroys the macula with following loss of central vision. The disease has many similarities with age-related macula degeneration which is the leading cause of blindness in the elderly. The work reported in Paper III describes refined localization and identification of the disease causing gene later named Bestrophin. Twelve European families were enrolled in the study, one of them was a four-generation family from Western Sweden.Noonan syndrome is a well-known genetic disorder, said to be inherited dominantly in 50% of the affected. Short stature in females and infertility in males, as well as symptoms from the head and neck, are the most common signs. Congenital heart malformations and progressive heart failure are the more serious symptoms of this condition. At least 3 genes may produce similar symptoms. The first identified PTPN11 gene answers for half of the cases. The Paper IV reports a Western Swedish five-generation family with 12 affected members. The PTPN11 locus was at first excluded in this family. The wide-genome scan with 224 DNA markers identified a likely locus on chromosome 1p21-p13. Further work is needed to identify the responsible gene.The tripeptidyl peptidase-2 gene (TPP2) codes for a large enzyme needed to degrade surplus proteins. The amino acid sequence of this enzyme, isolated from human red blood cells was at first decoded and the cDNA sequence later deduced. The Paper V describes how the gene encoding this enzyme was localized to chromosome band 13q32. No disease eventually produced by this gene is yet known but lethality in fetus may be one possible explanation.