1 Autosomal Polycystic Kidney Disease ! Student Name December 14th, 2018 Bio 2400.05 – Genetics Disease Report 2 Introduction Genetic disorders are a topic in biology that can not be avoided. The fact is that genetic disorders can happen in humans, plants or animal. No one and nothing are safe from a genetic disorder. A genetic disorder can appear in the first years of life or can appear much later in life when least expected. A basic principal of biology states that the behavior of chromosomes during the meiosis process can account for genetic inheritance patterns. There are many reasons for genetic disorders. To start it is important to understand what a genetic disorder is. It is a mutation in the genetic material of a person. The mutant gene is transmitted thru birth. These genetic mutations can create serious complications and even death. What is Autosomal Polycystic Kidney Disease? Polycystic Kidney Disease (PKD) is a genetic kidney disease which causes large benign cysts to form on the kidneys. The cysts are fluid filled cavities that can ultimately impede kidney function leading to degeneration of renal tissue and renal failure. Cysts can range anywhere from microscopic in size to several centimeters in diameter. A cyst begins as a protrusion of the nephron and can occur anywhere along its length. Most cysts detach from the nephron, and eventually enlarge and fill with either clear fluid or fluid that contains blood or white blood cells. Autosomal polycystic kidney disease (APKD) is one of the most common forms of polycystic kidney disease. There are two types of PKD; autosomal dominant and autosomal recessive. Autosomal dominant PKD, or ADPKD, is the most common form of PKD and typically manifests itself in middle aged adults while autosomal recessive PKD is less 3 common and typically manifests itself in childhood. Autosomal recessive PKD is the more serious form and often leads to death in infancy or early childhood. For a person to inherit ADPKD, it takes a mutated gene from only one parent, while it takes a mutated gene from both parents for a person to inherit ARPKD (figure 1 and 2). Figure 1: Explanation of Autosomal Dominant lineage Figure 2: Explanation of Autosomal Recessive lineage When PKD causes kidneys to fail – which usually happens after many years – the patient requires dialysis or kidney transplantation. About one-half of people with the major type of PKD progress to kidney failure, also called end-stage kidney disease. PKD can also cause cysts in the liver and problems in other organs, such as the heart and blood vessels in the brain. It is among the most common genetic diseases that are life threatening. PKD affects 12 and 1/2 million people worldwide. There are over 600,000 people with PKD in the US, the number could actually be higher as many adults who have PKD do not yet exhibit symptoms. It is the 4th leading cause of kidney failure. Each child born to a parent with the gene for ADPKD has a 50% 4 chance of inheriting the disease. It is present at birth in 1 in 400 to 1 in 1,000 babies. ADPKD occurs in individuals and families worldwide and in all races. Diagram showing the relative contributions of various factors to the resulting phenotypes in autosomal dominant (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). Body: Proteins and Normal Functions and What could go wrong? ADPKD is genetically heterogeneous with two genes identified: PKD1 (chromosome region 16p13.3; around 85% cases) and PKD2 (4q21; around 15% cases). Several genetic mechanisms probably contribute to the phenotypic expression of the disease. Although there is evidence for a two-hit mechanism (germline and somatic inactivation of two PKD alleles) explaining the focal development of renal and hepatic cysts, haploinsufficiency is more likely to account for the vascular manifestations of the disease. Additionally, new mouse models homozygous for Pkd1 5 hypomorphic alleles 22 and 23 and the demonstration of increased renal epithelial cell proliferation in Pkd2 +/− mice suggest that mechanisms other than the two-hit hypothesis also contribute to the cystic phenotype. There is large interfamilial and intrafamilial variability in ADPKD. Most individuals with PKD1 mutations have renal failure by age 70 years, whereas more than 50% of individuals with PKD2 mutations have adequate renal function at that age (mean age of onset of end-stage renal disease: 54·3 years with PKD1; 74·0 years with PKD2). The significant intrafamilial variability observed in the severity of renal and extrarenal manifestations points to genetic and environmental modifying factors that may influence the outcome of ADPKD, and results of an analysis of the variability in renal function between monozygotic twins and siblings support the role of genetic modifiers in this disease. It is estimated that 43–78% of the 6 variance in age to ESRD could be due to heritable modifying factors, with parents as likely as children to show more severe disease in studies of parent-child pairs. ADPKD is genetically heterogeneous, with two genes identified: PKD1 (16p13.3) and PKD2 (4q21). PKD1 is the major locus, accounting for approximately 85% of families. Further genetic heterogeneity has been suggested by unlinked families, but no further genes have been identified, and, indeed, there is doubt about the existence of a PKD3. PKD1 has 46 exons and encodes a large protein, polycystin-1 (4303 amino acids). Exons 1 to 33 lie in a complex genomic region that is reiterated approximately six times further proximally on chromosome 16. Similarity between PKD1 and these pseudogenes means that locus-specific amplification methods are required to analyze PKD1. PKD2 has 15 exons and encodes polycystin-2 (968 amino acids). A high level of allelic heterogeneity is found for both genes, with a total of 270 different mutations reported for PKD1 and 73 for PKD2 (up to 2003; according to Human Gene Mutation Database [http://www.hgmd.org]). More complete information in the ADPKD Mutation Database (http://pkdb.mayo.edu) describes 298 PKD1 and 106 PKD2 mutations. Most mutations are unique to a single family. For PKD1, 200 (67%) mutations are definitely pathogenic (nonsense, frameshifting, or splicing), and 98 (33%) are missense or other in-frame events. For PKD2, a larger proportion of mutations are truncating, 97 (91.5%), and only nine (8.5%) are inframe. In a recent screen of 202 well-characterized probands with ADPKD (the Consortium of Radiologic Imaging Study of PKD [CRISP] population), comprehensive mutation analysis of both genes identified a probable mutation in almost 90% of cases (Rosetti et al., submitted). This study involved a systematic algorithm for scoring the likely pathogenicity of missense and other 7 atypical changes. Although these methods are far from perfect for mutation prediction, they do show the prospects for molecular diagnostics in ADPKD. Although gene-based diagnostics are not necessary in every patient with ADPKD (renal imaging is a reliable diagnostic tool in most), it can be helpful in childhood cases with unknown etiology and critical for young livingrelated donors for whom imaging data are less reliable. It is likely to become more important as therapies are developed. There is little evidence of genetic heterogeneity in typical ARPKD cases. The disease gene, PKHD1 (6p21), has 67 exons and encodes the large protein fibrocystin (4074 amino acids) (30,31). As in ADPKD, many different PKHD1 mutations cause ARPKD. To date, 305 different mutations are listed in the ARPKD/PKHD1 Mutation Database (http://www.humgen.rwth-aachen.de), accounting for more than 700 mutant alleles. In this case, only approximately 40% are predicted to truncate the protein, with approximately 60% missense. Several studies have used detailing algorithms to assess the pathogenicity of these changes to aid their use for diagnostics. Approximately one third of PKHD1 mutations are unique to a single family. Some ancestral mutations are common in particular populations, and one mutation, T36M, of Northern European origin, accounts for approximately 17% of mutant alleles. Molecular diagnostics for ARPKD is 8 important for prenatal testing, including preimplantation genetic diagnostics, and for establishing a firm diagnosis. Summary Polycystic kidney disease (PKD) is a genetic disorder characterized by the growth of numerous cysts in both kidneys. The cysts are filled with fluid. The progressive expansion of PKD cysts slowly replaces much of the normal mass of the kidneys and can reduce kidney function and lead to kidney failure. The treatment for PKD is aimed at treating the kidney and non-kidney symptoms. Blood pressure is followed regularly. High blood pressure is treated with medication. Pain in the area of the kidneys is treated as needed with pain medications, and for chronic pain, with antidepressants. When standard methods to treat kidney pain do not work, then removing the fluid in the kidney cysts may be done. When kidney function starts to decline, treatment is aimed at slowing down the progression to kidney failure. This involves controlling high blood pressure, restricting protein in the diet, controlling build up of acid (acidosis) and preventing elevated levels of phosphate (hyperphosphatemia). When individuals with ADPKD develop renal failure, they need to have dialysis or a renal transplant. Studies have shown that individuals with ADPKD do better on dialysis than individuals with kidney failure from other causes. It is now possible to start dissecting the relative importance of various genetic and environment factors to the presentation and progression of PKD. In ADPKD, the gene involved is a major predictor of severity, with genetic background and environmental factors moderately involved and allelic effects probably less important. In ARPKD, the combination of alleles is a major factor in disease severity. While candidate association studies have been disappointing for 9 finding genetic modifiers in human PKD, recent development of high-resolution singlenucleotide polymorphism arrays and mapping the haplotype block structure of the human genome make genome-wide association studies to find modifiers now a reality. Equally important are the larger populations that now are being assembled for observational and clinical trials of ADPKD that will provide the clinically well-characterized groups that are required for these studies. Though there is no way to prevent inherited conditions you can do things to avoid complications. In PKD it’s important to keep your kidneys as healthy as possible. The best way to do that is to manage your blood pressure, eat a diet low in salt, low fat and limit protein. Eat more whole grains, fresh fruits and vegetables avoid alcohol and smoking. Exercise, exercise, exercise! Exercising on a regular basis for at least 30 minutes a day for at least 5 days a week. This helps manage your blood pressure as well as avoid other complications including obesity. 10 References “2018 AMI Online Salon.” AMI 2018 Meeting, meetings.ami.org/2018/project/autosomaldominant-polycystic-kidney-disease-etiology-and-pathogenesis/. Chapin, Hannah C., and Michael J. Caplan. “The Cell Biology of Polycystic Kidney Disease.” JCB, Rockefeller University Press, 15 Nov. 2010, http://jcb.rupress.org/content/ 191/4/701/. Hossain, Ibrahim. “Prepare for Medical Exams.” Primary Infertility Case Study, 1 Jan. 1970, prepareformedicalexams.blogspot.com/2016/11/screening-for-autosomal-dominant.html. Kolb. Robert J. and Nauli, Surya M. “Ciliary dysfunction in polycystic kidney disease: an emerging model with polarizing potential.” 1 May 2008, https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC3146368/ “Learning About Autosomal Polycystic Kidney Disease.” National Human Genome Research Institute (NHGRI), www.genome.gov/20019622/learning-about-autosomal-polycystickidney-disease/. “New Insights into the Molecular Pathophysiology of Polycystic Kidney Disease.” NeuroImage, Academic Press, www.sciencedirect.com/science/article/pii/S0085253815460703. “Polycystic Kidney Disease.” Physiopedia, www.physio-pedia.com/Polycystic_Kidney_Disease. Rossetti, Sandro, and Peter C. Harris. “Genotype–Phenotype Correlations in Autosomal Dominant and Autosomal Recessive Polycystic Kidney Disease.” American Society of Nephrology, American Society of Nephrology, 1 May 2007, jasn.asnjournals.org/content/ 18/5/1374. Breast Cancer Mutations in BRCA 1 and BRCA 2 genes ! Student Name Genetic Disorder Report December 11, 2018 Bio 2400 Dr. Lucy Liu Introduction Breast cancer is the most common form of cancer found in women worldwide, on average, 1 in 8 women will be diagnosed with breast cancer in their life (NBCF 2018). Cancer cells are developed when a healthy cell becomes mutated from damaged DNA, when there is an error such as cell reproduction when cells are not needed or when damaged cells do not die off as they should. When this happens, an accumulation of cells can occur and develop a lump or mass also known as a tumor. Tumors can be benign (non-cancerous) or malignant (cancerous) but with benign tumors, they are unable to metastasize and invade nearby tissues, they develop at a much slower rate and are not considered as serious of a health concern as cancerous tumors. Malignant cells have the capability to reproduce at faster rates than normal cells and often invade neighboring cells and tissues; these cells can break off and enter the blood stream and travel to other organs and tissues. Risks for developing cancer can be either environmental, genetic or a combination. There are many risk factors including the genetic mutation of the breast cancer genes BRCA 1 and BRCA 2 (BReast CAncer genes). Everyone has these genes and when there is no genetic mutation, they play an important role in helping prevent breast cancer (NBCF 2018). ! BRCA 1 and BRCA 2 The BRCA genes are important because they are tumor suppressor proteins that are designed to help repair DNA that has been damaged and ensuring the stability of the cell’s genetic material (National Cancer Institute 2018). Studies have shown that BRCA 1 and BRCA 2 help to repair the double-strand breaks and initiate homologous recombination (Yoshida 2005). BRCA 1 interacts with the nucleus of healthy cells to mend damaged DNA and may possibly play an important role in embryonic development. Another important job of these tumor suppressor proteins is to keep the cells from growing too rapidly which is common in metastasized cells (BRCA, ACOG 2018). Gene Mutation When a mutation in the gene occurs, it can increase the risk of breast cancer, in addition to other predetermined risks such as heredity. A genetic mutation in the BRCA gene occurs when that gene’s DNA has become damaged, or from inheritance of a gene mutation from either parent on the X chromosome. Due to the mutation, people who have a BRCA gene mutation, are more likely to develop breast cancer in comparison to people who do not have the BRCA mutation (NBCF 2018). Currently, over 1,800 mutations have been identified in the BRCA1 gene and most of these are associated with an increased risk of breast cancer in both men and women, along with other types of cancer. With BRCA 1 gene mutations, it leads to the production of an abnormally short version of the protein or prevents any protein from being made from one copy of the gene and these defects allow cells to grow and divide at a faster, uncontrollable rate which ! results in a mass or tumor (BRCA, NIH 2018). Anyone who has the BRCA gene mutation or is a carrier, is at a higher risk of developing cancer, more often breast or ovarian cancer. Although one may be a carrier, it does not always mean they will develop cancer, and people without the mutation may also develop cancer. Being affected by the BRCA gene mutation increases one’s risk of cancer to 45-85%, when someone without the mutation will have about a 12% risk of developing cancer in their lifetime (BRCA, ACOG 2018). It has been found that there is also an increased risk of cancer in the fallopian tubes, peritoneum, pancreas, and skin (melanoma) in women and increased risk of breast, prostate, and pancreatic cancer in men (BRCA, ACOG 2018). If the gene mutation is hereditary, there is a 50% chance of inheriting the BRCA 1 or BRCA 2 mutation if one of the parents is a carrier and the effects of the mutation are still seen even if the other gene is normal. It is also common for a loss of heterozygosity in the chromosomes which makes the carrier become more likely to develop cancer in their lifetime because their normal chromosome loses the healthy region. According to the National Cancer Institute, there are populations that have a higher prevalence of the BRCA 1 and BRCA 2 mutation such as people of Ashkenazi Jewish descent, as well as Norwegian, Dutch and Icelandic people. It is common for African Americans, Hispanics, Asian Americans, and non-Hispanic whites to have a specific harmful mutation of BRCA 1 and BRCA 2 (National Cancer Institute 2018). In women and men that have the BRCA 1 or BRCA 2 gene mutation, if they develop cancer and overcome it with treatment, they have a higher chance of developing another form of cancer or potentially the breast cancer may return. While many people have the risk of cancer due to this mutation, it has been reported that less than 10% of women diagnosed with breast cancer have a BRCA mutation (NBCF 2018). Early detection and preventative care Genetic testing for BRCA 1 and BRCA 2 is a possibility for those who believe or know their family has a history of breast cancer. Early detection is one ideal way to overcome the obstacle of potential cancer, but not everyone has the advantage to do so. There are several different tests available that require DNA from either blood or saliva, the DNA sample is taken and sent to the lab for analysis and generally takes a month for the results to come back (National Cancer Institute 2018). Doctors can test anyone for the BRCA genetic mutations but do not recommend it for anyone who does not have a familial history or is not considered high risk of carrying the BRCA mutation. If there is any family history it is beneficial to be tested and know if one is a carrier or not because whether you develop cancer or are a carrier of this mutation, it can still be passed on to their children. Preventative actions are one of the most important things that can be done to help reduce or prevent the risks of cancer. While, many cancers can go undetected for years with or without symptoms, it is still important to see a physician regularly for optimal health. Many do not have the opportunity to do so for many reasons such as financial, economic, social or even cultural aspects of their lives. Testing is important because with early detection, there is a higher chance of overcoming cancer compared to finding out when it is too late. For women with the BRCA mutation it is recommended to have a breast exam every 6-12 months and to have an annual breast imaging with an MRI machine beginning at 25 years of age, and MRI and mammography beginning at 30 years of age (BRCA, ACOG 2018). In addition to early testing and screening, there are other preventative care options available such as prophylactic or risk-reducing surgery where any known at-risk tissue is removed whether it be part of a breast, a full breast, or even both breasts commonly known as a mastectomy or risk-reducing bilateral mastectomy, respectively. This method can be proactive in reducing the risk of developing breast cancer but cannot provide a guarantee as there can be the possibility of some at-risk tissue that remains in the chest (National Cancer Institute 2018). There are also some medications that have shown to reduce the risk of breast cancer with the BRCA 2 mutation such as Tamoxifen. This drug was created to block the effects of estrogen on cancer cells that respond to the hormone and is only efficient with BRCA 2 because most breast cancer tumors from BRCA 2 are a result from a response to estrogen (BRCA, ACOG 2018). Summary BRCA 1 and BRCA 2 are tumor suppressor genes that enter a cell’s nucleus to repair any damaged DNA to create a healthy cell. There are almost 2,000 variations in the genetic mutation of these genes and it can be from damaged DNA, an error in duplication, loss of heterozygosity or inherited genetically from a parent. Where there is a mutation, the BRCA 1 and BRCA 2 genes are unable to repair the damaged DNA which results in damaged cells that can divide and reproduce at a rapid rate to form a mass or tumor. This genetic mutation is hereditary and can be passed to offspring with a 50% chance of being a carrier if one of the parents is affected or a carrier of the BRCA mutations. Due to the mutation, one has a higher risk of developing breast cancer than someone without the genetic mutation, although it does not guarantee cancer will be present in the individual. The cause of the mutation is not known but with early detection and testing, people can learn if they have the mutation or not and take appropriate action of choice to reduce their risk of cancer. The BRCA 1 and BRCA 2 mutations also increase the risk of developing a secondary form of cancer, especially if they have been diagnosed with breast cancer and overcome it. Unfortunately, there is no way to reverse the mutation yet but prevention and treatment is available to help reduce the risk of developing cancer and increase the chance of survival. References “BRCA 1 and BRCA 2 Mutations.” ACOG, The American College of Obstetricians and Gynecologists, Aug. 2018, www.acog.org/Patients/FAQs/BRCA1-and-BRCA2Mutations. “BRCA1 Gene – Genetics Home Reference – NIH.” U.S. National Library of Medicine, National Institutes of Health, Oct. 2018, ghr.nlm.nih.gov/gene/BRCA1#resources. “BRCA Mutations: Cancer Risk & Genetic Testing.” National Cancer Institute, National Cancer Institute, 30 Jan. 2018, www.cancer.gov/about-cancer/causes-prevention/genetics/brcafact-sheet. Nbcf. “BRCA: The Breast Cancer Gene :: The National Breast Cancer Foundation.” Www.nationalbreastcancer.org, National Breast Cancer Foundation, Inc., 2018, www.nationalbreastcancer.org/what-is-brca. Yoshida, Kiyotsugu, and Yoshio Miki. “Role of BRCA1 and BRCA2 as Regulators of DNA Repair, Transcription, and Cell Cycle in Response to DNA Damage.” Cancer Science, vol. 95, no. 11, 19 Aug. 2005, pp. 866–871., doi:10.1111/j.1349-7006.2004.tb02195.x. Examples of Autosomal Recessive Traits © Cengage Learning 2016 Missense Mutation in Sickle Cell Anemia © Phototake/Alamy Normal red blood cells © Phototake/Alamy 10 μm Sickled red blood cells 10 μm (a) Micrographs of red blood cells NORMAL : NH2 – VALINE – HISTIDINE – LEUCINE – THREONINE – PROLINE – GLUTAMIC ACID – GLUTAMIC ACID… SICKLE CELL : NH2 – VALINE – HISTIDINE – LEUCINE – THREONINE – PROLINE – VALINE– GLUTAMIC ACID… (b) A comparison of the amino acid sequence between normal β-globin and sickle-cell β-globin Genes Traits Normal Hemoglobin (HbA) and Sickle Cell Hemoglobin (HbS) Normal hemoglobin (HbA) DNA mRNA Amino acid Hemoglobin in sickle cell anemia (HbS) DNA mRNA Amino acid © Cengage Learning 2016 Sickle Cell Disease (a) Normal red blood cell (b) Sickled red blood cell (a): © Mary Martin/Science Source (b): © Science Source © McGraw-Hill Education. 4-‹#› Overdominance (1 of 4) Overdominance is the phenomenon in which a heterozygote is more vigorous than both of the corresponding homozygotes • It is also called heterozygote advantage Example = Sickle-cell anemia • Autosomal recessive disorder • Affected individuals produce abnormal form of hemoglobin • Two alleles • HbA ! Encodes the normal hemoglobin, hemoglobin A • HbS ! Encodes the abnormal hemoglobin, hemoglobin S © McGraw-Hill Education. 4-‹#› Overdominance (2 of 4) HbSHbS individuals have red blood cells that deform into a sickle shape under conditions of low oxygen tension • This has two major ramifications • Sickling phenomenon greatly shortens the life span of the red blood cells • Anemia results • Odd-shaped cells clump • Partial or complete blocks in capillary circulation • Thus, affected individuals tend to have a shorter life span © McGraw-Hill Education. 4-‹#› Overdominance (3 of 4) Why is the sickle cell allele found at a fairly high frequency in parts of Africa where malaria is found? Malaria is caused by a protozoan, Plasmodium • This parasite undergoes its life cycle in two main parts • One inside the Anopheles mosquito • The other inside red blood cells • Red blood cells of heterozygotes, are likely to rupture when infected by Plasmodium • This prevents the propagation of the parasite © McGraw-Hill Education. 4-‹#› Overdominance (4 of 4) HbAHbS individuals have an “advantage” over • HbSHbS, because they do not suffer from sickle cell anemia • HbAHbA, because they are more resistant to malaria © McGraw-Hill Education. 4-‹#› I -1 II -1 III -1 I-2 II -2 III -2 III -3 II -3 II -4 III -4 III -5 (a) Human pedigree showing cystic fibrosis II -5 III -6 III -7 The Function of CFTR CFTR encodes a 170 kDa, membrane-based protein with an active transport function Cystic fibrosis transmembrane conductance regulator (CFTR) The ΔF508 Mutation A 3 base pair deletion called ΔF508 is the most common mutation causing cystic fibrosis The mutation results in the deletion of a single amino acid (Phe) at position 508. From Mutation to Disease The mutant form of CFTR prevents chloride transport, causing mucus build-up Mucus clogs the airways and disrupts the function of the pancreas & intestines. Autosomal Recessive Inheritance • Tay-Sachs Disease (TSD) – Affected individuals appear healthy at birth, but then develop neurodegenerative symptoms at 4 to 6 months • Cerebral degeneration, blindness and loss of motor function – TSD patients typically die at 3 or 4 years of age – TSD is about 100 times more frequent in Ashkenazi (eastern Europe) Jewish populations than in others – TSD is the result of a mutation in the gene that encodes the enzyme hexosaminidase A (hexA) • HexA breaks down a category of lipids called GM2gangliosides – An excessive accumulation of this lipid in cells of the CNS causes the neurodegenerative symptoms – TSD is inherited in an autosomal recessive manner Autosomal Recessive Inheritance I-1 II-1 III-1 IV-1 II-3 II-2 III-2 IV-2 III-3 III-4 I-2 II-4 II-5 II-6 II-7 II-8 II-9 III-5 III-6 III-7 III-8 III-9 III-10 III-11 , Tay-Sachs disease , Carrier , Normal IV-3 IV-4 IV-5 IV-6 IV-7 IV-8 IV-9 A family pedigree of Tay-Sachs disease II-10 II-11 Examples of Autosomal Dominant Traits © Cengage Learning 2016 Autosomal Dominant Inheritance • Huntington Disease (HD) – The major symptom of the disease is the degeneration of certain types of neurons in the brain – This leads to personality changes, dementia and early death (usually in middle age) – HD is the result of a mutation in a gene that encodes a protein termed huntingtin – This causes an aggregation of the protein in neurons – HD is inherited in an autosomal dominant manner II -1 II -2 III-1 I -1 I -2 II -4 II -5 II -3 III-2 A family pedigree of Huntington disease II -6 II -7 III-3 III-4 Pedigree Analysis of an Autosomal Dominant Trait © Cengage Learning 2016 Marfan Syndrome: An Example of an Autosomal Dominant Trait ▪ Incidence ▪ 1 in 10,000 individuals ▪ 25% of cases have no familial history, indicating a high mutation rate ▪ Genetics and phenotype ▪ Mutations in the fibrillin gene (FBN1) on chromosome 15 cause defective and weakened connective tissue © Cengage Learning 2016 Marfan Syndrome: Genetics and Phenotype (cont’d.) Affects the skeletal system, cardiovascular system, heart, and eyes ▪ Individuals are tall and thin, with long arms and legs and thin fingers ▪ © Cengage Learning 2016 Affected with DMD I-1 I-2 II-1 II-2 II-3 II-4 III-1 III-2 III-3 IV-1 IV-2 IV-3 III-4 IV-4 Unaffected, presumed heterozygote II-5 II-6 III-5 III-6 III-7 III-8 IV-5 IV-6 IV-7 Human Pedigree for Duchenne muscular dystrophy-Affected individuals are shown with filled symbols. Female carriers are shown with half-filled symbols. X-linked Inheritance: color-blindness mother not color-blind functional redgreen allelles X X nonfunctional redgreen allelles egg X father not color-blind XX XX daughters are not color-blind XY XY one son is color-blind sperm Y X-Linked Recessive Inheritance © Cengage Learning 2016 Examples of X-Linked Recessive Traits © Cengage Learning 2016 Muscle Dystrophy: An Example of X-Linked Recessive Trait: A group of genetic diseases associated with progressive degeneration of muscles ▪ Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) have X-linked recessive inheritance patterns ▪ ▪ Both caused by mutations in the dystrophin gene ▪ DMD is more severe, because the dystrophin protein is defective or absent, while individuals with BMD have partially functional dystrophin proteins © Cengage Learning 2016 Molecular Characteristics of DMD Proteins Bone Tendon Muscle Muscle cell membrane Dystrophin Actin (thin) filament Actin (thin) filament Muscle filaments Muscle fiber (cell) Bundle of muscle fibers © Cengage Learning 2016 Distribution of Dystrophin in Muscle Cells ▪ (a) normal cells © Cengage Learning 2016 (b) from a patient with DMD Color Blindness: An Example of an X-linked Recessive Trait Defective color vision caused by reduction or absence of visual pigments ▪ Three forms: red, green, and blue blindness ▪ About 8% of the male population in the US affected ▪ © Cengage Learning 2016 Molecular Medicine: Nuclear Lamina Diseases Hutchinson-Gilford progeria This mutant gene encodes a defective mRNA With a 150-base pair deletion in exon 11 Due to aberrant splicing Retinoblastoma • Diagnosis: “Cat’s eye” reflection (leukocoria) in affected eye. • Most common cancer of infants and children (1/20,000 U.S. live births). • Survival > 90% with early diagnosis and treatment. • Individuals at greater risk of developing other cancers. Mutations in the RB tumor suppressor gene can lead to retinoblastoma. Sporadic, nonfamilial cases Familial cases Breast Cancer ▪ Mutations in BRCA1 and BRCA2 genes can predispose women to breast and ovarian cancer, depending on genotype ▪ BRCA1 and BRCA2 mutations account for only 15-20% of all breast cancer cases BRCA2 BRCA1 © Cengage Learning 2016 13 17 BRCA1 and BRCA2 are DNA Repair Genes ▪ BRCA1 and BRCA2 ▪ Encode nuclear proteins ▪ Expression is highest at the G1/S checkpoint in rapidly dividing cells ▪ BRCA1 ▪ Tumor suppressor gene ▪ Normally repairs breaks in DNA during DNA replication ▪ Mutant BRCA1 does not assist in DNA repair ▪ Accumulation of DNA mutations ▪ Cell becomes cancerous © Cengage Learning 2016 BRCA Mutation Causes Breast Cancer , , Homozygous normal Heterozygous for BRCA-1 mutation, affected Heterozygous for BRCA-1 mutation, unaffected Normal cell BRCA-1 BRCA-1 BRCA-1 BRCA-1 (Inherited mutation) (Occurs in a somatic cell) (Inherited mutation) Heterozygote – cell has one functional copy of BRCA-1 (a) Pedigree for familial breast cancer Cancer cell Loss of heterozygosity – cell has zero functional copies of BRCA-1 (b) Development of cancer at the cellular level Cancer Prevention: 2015: removal of ovaries 2013: double mastectomy High Risk of BRCA Mutation ▪ Inherited a mutant BRCA1 gene from her mother ▪ 87% risk of breast cancer ▪ 50% risk of ovarian cancer ▪ Her mother had breast cancer and died of ovarian cancer at the age of 56 ▪ Her mother’s mother was also diagnosed with ovarian caner ▪ Risk dropped to 5% of developing breast cancer after double mastectomy Deficiencies ■ The phenotypic consequences of deficiencies depends on the ■ ■ ■ 1. Size of the deletion 2. Chromosomal material deleted ■ Are the lost genes vital to the organism? When deletions have a phenotypic effect, they are usually detrimental ■ For example, the disease cri-du-chat syndrome in humans ■ Caused by a deletion in the short arm of chromosome 5 Cri du chat syndrome ▪ Associated with an array of p 15.3 15.2 15.1 Larynx development Nervous system; CTNND2 gene 14 malformations, the most characteristic of which is an infant cry that resembles a meowing cat due to defects q in the larynx 5 © Cengage Learning 2016 Deleted region © Biophoto Assocates/Science Source/Photo Researchers (a) Chromosome 5 © Jeff Noneley (b) A child with cri-du-chat syndrome Simple Translocations ■ In simple translocations the transfer of genetic material occurs in only one direction ■ These are also called unbalanced translocations ■ Unbalanced translocations are associated with phenotypic abnormalities or even lethality ■ Example: Familial Down Syndrome ■ ■ In this condition, the majority of chromosome 21 is attached to chromosome 14 The individual would have three copies of genes found on a large segment of chromosome 21 ■ exhibiting the characteristics of Down syndrome ➢The long arm of chromosome 21 has been translocated to chromosome 14 ➢The individual also carries two normal copies of chromosome 21 2 1 3 6 7 8 13 14 15 19 20 9 10 16 21 22 4 5 11 12 17 18 X Y (c) Child with Down syndrome (b) Karyotype of a male with familial Down syndrome What Are Some Consequences of Aneuploidy? ▪ Major cause of miscarriages and birth defects ▪ Only trisomy 13, 18 and 21 occur with any frequency in live births; the rest are eliminated by miscarriage as pregnancy progresses ▪ Associated with many cancers, especially leukemia © Cengage Learning 2016 Trisomy 21: Down Syndrome (47, +21) 1 in 800 live births ▪ Leading cause of childhood intellectual disability and heart defects ▪ © Cengage Learning 2016 Trisomy 21: Down Syndrome (47, +21) (cont’d.) ▪ Despite susceptibility to many health problems, individuals with Down syndrome can live productive lives and may survive to 50 years of age © Cengage Learning 2016 What are the Risks for Autosomal Trisomy? ▪ While the exact cause of autosomal trisomy is unknown, many factors may be involved, including: ▪ Genetic predisposition ▪ Exposure to radiation ▪ Viral infection ▪ Abnormal hormone levels © Cengage Learning 2016 Maternal Age: Major Risk for Autosomal Trisomy ▪ Maternal age is a major risk factor ▪ 94% of trisomy 21 nondisjunctions occur in the mother, most in meiosis I ▪ Advanced maternal age is a risk factor for trisomy 21 and other autosomal aneuploidies © Cengage Learning 2016 Maternal Age and Trisomy 21 35 18 14 Risk for Down syndrome 12 30 Maternal age and trisomic conceptions 25 15 10 P er ce nt a g e of cli ni ca lly re c o g ni ze d pr e g n a n ci es Trisomy 21/1,000 births 16 8 10 6 4 5 2 15 16 18 20 22 24 26 28 30 15 20 25 30 35 40 >44 Maternal age (a) © Cengage Learning 2016 Maternal age (b) 32 34 36 38 40 ≥42 ■ Some human aneuploidies are influenced by the age of the parents ■ Infants with Down syndrome (per 1000 births) ■ Older parents more likely to produce abnormal offspring Example: Down syndrome (Trisomy 21) ■ Incidence rises with the age of either parent, especially mothers 90 80 70 60 50 40 30 20 10 0 1/12 1/32 1/1925 1/1205 1/885 1/365 20 25 30 35 Age of mother 1/110 40 45 50 Why is Maternal Age a Risk Factor? ▪ Duration of meiosis I ▪ Primary oocytes develop during embryonic development and are arrested in prophase of meiosis I at birth ▪ The chance for intracellular or environmental factors to cause damage to oocytes increases the longer they are arrested in meiosis I © Cengage Learning 2016 Why is Maternal Age a Risk Factor? (cont’d.) ▪ Maternal selection ▪ Chromosomally abnormal embryos are typically preventing from implanting in the uterus ▪ This maternal selection may become less effective as women age, leading to more aneuploid births in older women © Cengage Learning 2016 Sex Development May Go Awry Chromosomal anomalies affect growth and fertility. • Klinefelter syndrome (XXY, XXXY): male, tall, low testosterone, small genitals, low sperm count • Turner syndrome (XO): female, short, lack normal ovaries, require assistance to enter puberty • XYY syndrome: male, may have genital anomalies, atypical cerebral cortex development • Triple-X syndrome: female, mild cognitive deficits, low fertility Sex Chromosome Aneuploidy More common than autosomal aneuploidy ▪ Involves both X and Y chromosomes ▪ At least one copy of an X chromosome is needed for human survival ▪ ▪ 44,-XX and 45,Y are not observed in miscarriages; therefore, these must be eliminated early in pregnancy ▪ Additional copies of the X or Y chromosome interfere with normal development © Cengage Learning 2016 Turner Syndrome (45,X) Monosomy of the X chromosome ▪ The only viable monosomy in humans ▪ 1 in 10,000 female births ▪ © Cengage Learning 2016 Turner syndrome: short stature Dr. Catherine Ward-Melver is a geneticist, and president of the Turner Syndrome Society Turner Syndrome (45,X) (cont’d.) ▪ Can result from meiotic or mitotic nondisjunction; no association with maternal age ▪ Individuals are sterile, and display some unique physical characteristics, but have no intellectual disabilities © Cengage Learning 2016 Klinefelter Syndrome (47, XXY) ▪ ▪ ▪ 1 in 1,000 male births Both maternal and paternal age are risk factors Characterized by some fertility problems but few additional symptoms © Cengage Learning 2016 XYY Syndrome (47,XYY) ▪ 1 in 1,000 male births ▪ 0.1% of males in the general population, but much higher percentage in psychiatric and penal institutions ▪ Affected individuals are usually taller than normal and some, but not all, have personality disorders © Cengage Learning 2016 XY Girl: My Life with Androgen Insensitivity Syndrome katie Baratz Dalke a psychiatrist practicing in Philadelphia She graduated from the School of Medicine at the University of Pennsylvania in 2011 Sex Development May Go Awry The gonads or genitals may be sexually ambiguous. • Gonadal intersexuality: possession of ovarian and testicular tissue, most look like women, usually infertile • Androgen Insensitivity Syndrome (AIS): XY “females,” androgen receptors are defective or absent, failing to respond to the testosterone, lack reproductive tract, shallow vagina, infertile • Congenital Adrenal Hyperplasia (CAH): XX fetus that experienced large amounts of androgens, partial masculinization of genitals. Most of these children are raised as girls, but some children with very marked masculinization are raised as boys. CANCER • Overview • Genetic Basis of Cancer • Oncogenes • Tumor-Supressor Genes • Targeted Cancer Therapy Estimated Cancer Cases © Cengage Learning 2016 Age is a Leading Risk Factor for Cancer Cancer deaths (per 100,000) 10,000 1,000 100 KEY 10 Male Female Age groups in years © Cengage Learning 2016 + 85 4 –8 75 4 –7 65 4 –6 55 4 45 –5 44 – 4 35 –3 25 4 –2 20 9 –1 15 4 10 –1 9 5– 1– 4 44 Maternal age (a) © Cengage Learning 2016 Maternal age (b) 32 34 36 38 40 ≥42 ■ Some human aneuploidies are influenced by the age of the parents ■ Infants with Down syndrome (per 1000 births) ■ Older parents more likely to produce abnormal offspring Example: Down syndrome (Trisomy 21) ■ Incidence rises with the age of either parent, especially mothers 90 80 70 60 50 40 30 20 10 0 1/12 1/32 1/1925 1/1205 1/885 1/365 20 25 30 35 Age of mother 1/110 40 45 50 Why is Maternal Age a Risk Factor? ▪ Duration of meiosis I ▪ Primary oocytes develop during embryonic development and are arrested in prophase of meiosis I at birth ▪ The chance for intracellular or environmental factors to cause damage to oocytes increases the longer they are arrested in meiosis I Nondisjunction in meiosis generates abnormal gametes © Cengage Learning 2016 Why is Maternal Age a Risk Factor? (cont’d.) ▪ Maternal selection ▪ Chromosomally abnormal embryos are typically preventing from implanting in the uterus ▪ This maternal selection may become less effective as women age, leading to more aneuploid births in older women © Cengage Learning 2016 Sex Chromosome Aneuploidy More common than autosomal aneuploidy ▪ Involves both X and Y chromosomes ▪ At least one copy of an X chromosome is needed for human survival ▪ ▪ 44,-XX and 45,Y are not observed in miscarriages; therefore, these must be eliminated early in pregnancy ▪ Additional copies of the X or Y chromosome interfere with normal development © Cengage Learning 2016 Turner Syndrome (45,X) Monosomy of the X chromosome ▪ The only viable monosomy in humans ▪ 1 in 10,000 female births ▪ 46-1 = 45 © Cengage Learning 2016 Missing one copy of X chromosome Turner syndrome: short stature Dr. Catherine Ward-Melver is a geneticist, and president of the Turner Syndrome Society Turner Syndrome (45,X) (cont’d.) ▪ Can result from meiotic or mitotic nondisjunction; no association with maternal age ▪ Individuals are sterile, and display some unique physical characteristics, but have no intellectual disabilities © Cengage Learning 2016 Turner Syndrome (45,X) ▪ Monozygotic twins, one having Turner syndrome ▪ Evidence of mitotic nondisjunction and the importance of two X chromosomes for normal development © Cengage Learning 2016 Klinefelter Syndrome (47, XXY) 46 + 1 = 47 1 in 1,000 male births ▪ Both maternal and paternal age are risk factors ▪ Characterized by some fertility problems but few additional symptoms ▪ © Cengage Learning 2016 Extra copy of X chromosome XYY Syndrome (47,XYY) 1 in 1,000 male births ▪ 0.1% of males in the general population, but much higher percentage in psychiatric and penal institutions ▪ Affected individuals are usually taller than normal and some, but not all, have personality disorders ▪ © Cengage Learning 2016 46 + 1 = 47 Extra copy of Y chromosome