遗传学英文课件：Monogenic disorder

1、Who am I？,Ages: 49; Native place: Xianyang, Shaanxi Province 1982.9.- 1986.6. Dept of Biology, Qinghai Normal University. B.S. 1986.7.- 1990.8. Middle School No. 2 of Delingha, Qinghai. 1990.9.- 1993.6. Dept of Medical Genetics, Shanghai Medical University. M.S. 1993.9.- 1996.7. State Key Lab of Gen

2、etic Engineering,Institute of Genetics, Fudan University. PhD 1996.8.- 1998.6. State Key Lab of Medical Neurobiology, Shanghai Medical University. Postdoctor 1998.7.-1999.11. State Key Lab of Genetic Engineering, Institute of Genetics, Fudan University. Associate Professor 1999.12.2004.8. Dept of Ge

3、netics,School of Medicine, Ningbo University. Associate Professor, Professor 2004.9.-, Dept of Cell Biology and Medical Genetics, SM, ZJU. Professor Papers in Molecular Medicine Reports, European Journal of Surgical Oncology, Thyroid, Gene, Anatomical Record, Familial Cancer, PLoS ONE, Genetic Testi

4、ng and Molecular Biomarkers, Prenatal Diagnosis, European Journal of Dermatology, American Journal of Ophthalmology, American Journal of Medical Genetics, British Journal of Dermatology, Journal of Cellular and Molecular Medicine, .,Major：epidermolytic palmoplantar keratoderma （EPPK）,Major：multiple

5、endocrine neoplasia 2A (MEN-2A),Nussbaum RL, et al. 张咸宁,等. Thompson Information on proteins: Biomedical literature: /entrez/ Human gene mutation database: Human disease genes list: http:/bioinfo.weizmann.ac.il/cards Genet

6、ic diagnosis: ,1966:MIM（McKusick VA, 1921-2008）,Last updated:7/31/2014. Numbers of reference: 88. Pubmed search references: 93564 !,Monogenic disorder(Patterns of single-gene disorder),ZHANG Xian-Ning, PhD Tel 88208367 Office: C303, Teaching Building 2

7、014/09,Genotype: The combination of alleles that an individual possesses. Phenotype: The physical characteristics of a cell or organism as defined by its genetic constitution.,Monogenic disorder,Allele: One of the variant forms of a gene at a particular locus, or location, on a cs. Different alleles

8、 produce variation in inherited characteristics such as hair color or blood type. Pedigree: A simplified diagram of a familys genealogy that shows family members relationships to each other and how a particular trait or disease has been inherited. Proband: The family member who first bring a family

9、to the attention of an investigator is proband. Pedigree symbols,Symbols Commonly Used in Pedigree Charts,Proband（先证者）: III-5 Pedigree drawing software：Progeny, etc.,Major Patterns of Monogenic Inheritance,Patterns of autosomal dominant inheritance (AD) Patterns of autosomal recessive inheritance (A

10、R) Patterns of X-linked dominant inheritance (XD) Patterns of X-linked recessive inheritance (XR) Patterns of Y-linked inheritance,Autosomal Dominant,AD,AD,AD,AD, requires mutation in only one allele to produce disease males and females equally affected family history usually positive, with affected

11、 members in each generation may show apparent generation skipping due to variable penetrance, variable expressivity, or appearance of a new mutation in the family Examples: Huntington disease, Marfan syndrome, neurofibromatosis, familial breast/ovarian cancer, myotonic dystrophy,AD,Huntington Diseas

12、e (HD),A progressive disorder of motor, cognitive, and psychiatric disturbances. The mean age of onset is 35 to 44 years and the median survival time is 15 to 18 years after onset. inherited in an AD manner. Offspring of an individual with a mutant allele have a 50% chance of inheriting the disease-

13、causing allele.,HD case-Woody Guthrie(1912-1967),Huntington Disease (HD),Frequency estimated to be about 3-7/100 000 in populations of western European descent. AD, Homozygotes for HD appear to have a similar age of onset to heterozygotes, but may exhibit an accelerated rate of disease progression.

14、The HD gene is the only gene associated with Huntington disease. A trinucleotide CAG repeat expansion in Exon 1 is the only mutation observed. Anticipation:,Trinucleotide CAG repeat sizes in HD,Normal 26 Mutable 27-35 Reduced penetrance 36-39 Fully penetrance 40,Anticipation,the phenomenon in which

15、increasing disease severity or decreasing age of onset is observed in successive generations, is known to occur in HD. occurs more commonly in paternal transmission of the mutated allele. The phenomenon of anticipation arises from instability of the CAG repeat during spermatogenesis. Large expansion

16、s (i.e., an increase in allele size 27 CAG repeats) occur almost exclusively through paternal transmission. Most often children with juvenile-onset disease have inherited the expanded allele from their fathers.,4p16.3, mapped in 1983. HD gene, isolated in 1993 using haplotype analysis of linkage dis

17、equilibrium. Huntingtin, a protein of 3144 amino acids with a predicted molecular mass of 348 kd. The CAG repeat in the HD gene is translated into an uninterrupted stretch of glutamine residues that when expanded may have altered structural and biochemical properties.,Huntington Disease (HD),Mary (3

18、5 y.o.), Samuel (30 y.o.), and Alice (29 y.o.) are siblings at 50% risk to inherit Huntington disease from their father, John, who was found to have a mutable normal allele when he was tested following diagnosis of his brother, Bart. All three siblings chose molecular genetic testing following genet

19、ic counseling and neurologic evaluation. All have normal neurologic examinations.,Clinical Case,What do these results mean?,Mary 38 CAG repeats,Samuel 35 CAG repeats,Alice 42 CAG repeats,Bart,John Mutable normal,Molecular Genetic Testing,Diagnosis,Samuel (35 repeats) is told that he has a mutable no

20、rmal allele. Expansions of 27-35 CAG repeats have never been associated with clinical symptoms of HD; however, his children are at some risk to inherit an allele with a larger allele size which could result in symptomatic HD.,Mary,Samuel (30 y.o.) 35 CAG repeats Mutable normal allele,Alice,Mary (38

21、repeats) is told that she has a reduced penetrance allele. Expansions of 36-40 CAG repeats may or may not cause symptoms of HD during a normal life span. The onset of symptoms may be later than typically observed. Marys children are at 50% risk for inheriting the abnormal allele, which could remain

22、in the reduced penetrance range or expand into the full penetrance range.,Mary (35 y.o.) 38 CAG repeats Reduced penetrance allele,Samuel,Alice,Alice (42 repeats) is told that she has a full penetrance allele. Expansions of 41 CAG repeats or greater are always associated with symptomatic HD if the in

23、dividual lives a normal life span. Alices children are at 50% risk to inherit the full penetrance allele and therefore to develop HD.,Mary,Samuel,Alice (29 y.o.) 42 CAG repeats Full penetrance allele,HD gene-Hero!,In 1983, HD was the first genetic disease to be localized to a chromosome location (4p

24、16.3) with RFLP linkage analysis. (Gusella et al.) Robertson:“The beginning of the end of dilemma?” (Nature) The HD gene, Huntingtin, was isolated in 1993 after a decade of intense collaborative efforts among many laboratories from various countries and officially designated HD. (Gusella et al.) Lit

25、tle:“Huntingtons disease: The end of the beginning” (Nature),Locations of Repeats,Richards COL1A2, 7q22.1) -Locus heterogeneity,bone fragility reduced life span short stature dentinogenesis hearing loss affects 1/10 000 individuals,OI type I,Blue sclerae Near normal height Fractures Hearing loss Dom

26、inant inheritance,OI type II,Severe bone compression Soft calvarium Blue sclerae Perinatal death New in family,OI type III,Very short Marked and progressivedeformity Blue or normal sclerae Dentinogenesis imperfecta Often non-ambulatory Often new in family,OI type IV,Normal sclerae Mild-moderate shor

27、t stature Fractures Dentinogenesis imperfecta Bone deformity Dominant inheritance,AD null or structural mutations in type I collagen a chain genes lead to different types of OI dominant negative effect haploinsufficiency germline mosaicism,Genetic Basis of Osteogenesis Imperfecta,Classic Ehlers-Danl

28、os syndrome(EDS),More than 70% have mutations in COL5A1 (9q34.2-q34.3) of which a third have premature termination codons Rare mutations in COL5A2 (2q31) Even rarer in COL1A1 (17q21.3-q22) 50% have a de novo mutation,Eric was 9 years old when he presented to Medical Genetics Clinic for chronic joint

29、 dislocation and child abuse. His past medical history was significant for child abuse, for which he was removed from his home on several occasions. On examination he had marked scarring of his forehead, chin, and knees. He had hemosiderin deposition on his shins with thin atrophic shiny skin. His j

30、oints were lax and he had pes planus with weight bearing and genu recurvatum. He could stick out his tongue and touch his nose. A diagnosis of Ehlers-Danlos type I was made and he was returned to his home,where he once again suffered abuse at the hands of his mother and her boy friend.,EDS type I,4.

31、5-year-old boy,Unusual Features of Autosomal Dominant Inheritance,Reduced penetrance Variable expressivity High frequency of new mutations,Autosomal Recessive(AR),AR,AR,AR,AR, requires mutation of both alleles to produce disease males and females equally affected higher frequency in consanguineous m

32、atings higher frequency of mutation carriers in particular ethnic groups family history often negative often associated with enzymatic defects causing metabolic disorders Examples: sickle cell disease, phenylketonuria, cystic fibrosis, spinal muscular atrophy, Wilson disease,AR,AR,Develop in persons

33、 who receive two copies of the mutant gene, one from each parent who is a carrier. Carrier: a person who has a recessive mutated gene, together with its normal allele. Carriers do not usually develop disease but can pass the mutated gene on to their children.,Sickle cell anemia,lethal disease in whi

34、ch a defect (Glu6Val) in 146 AA -hemoglobin, the oxygen-carrying pigment in the blood, causes Hb aggregation and distortion (sickling) and loss of red blood cells, producing damage to organs throughout the body 1st identified Hb disease 1/600 African Americans,HbS-CCT GTG GAG- -Pro Val Glu-,HbA-CCT

35、GAG GAG- -Pro Glu Glu-,6,Cystic Fibrosis ( CF ),Severe progressive disease of the bronchial system and gastrointestinal tract Disturbed function of a chloride ion channel by mutations of one gene, CFTR (Cystic fibrosis transmembrane conduction regulator) on 7q31.3, 24 exons, 6.5-kb transcript, 1480

36、amino acids. AR Disease incidence approx. 1:2000 in Caucasian.,CFTR Gene,1st gene identified by positional cloning Identified by the research group led by Dr. Lap-Chee Tsui (徐立之) at Toronto, Canada,- (1989) Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245: 1059

37、-1065. - (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245: 1066-1073. - (1989) Identification of the cystic fibrosis gene: genetic analysis. Science 245: 1073-1080.,CF,Other Examples of AR Disorders,Phenylketonuria ( PKU ): Gene locus

38、(PAH) : 12q22-24. Disease incidence 1:16000, cirrhosis of liver, galactosuria and mental retardation. Mutations in the gene for phenylalanine hydroxylase. Albinism: A pigmentless “white” phenotype, determined by a mutation in a gene coding for a pigment-synthesizing enzyme.,Spinal muscular atrophy (

39、SMA) A disorder characterized by degeneration of lower motor neurons and occasionally bulbar motor neurons leading to progressive limb and trunk paralysis as well as muscular atrophy. It is a clinically and genetically heterogeneous group of neuromuscular diseases. It is the second most common letha

40、l autosomal recessive disorder after cystic fibrosis in Caucasian populations with an overall incidence of 1 in 10000 live births and a carrier frequency of approximately 1 in 50.,Spinal muscular atrophy (SMA),Wilson disease: Cu toxicity, AR,Wilson SAK. Brain, 1912; 34:295-507,Wilson disease:Before/

41、After penicillamine therapy,X-linked Recessive (XR),XR,XR,XR,XR, due to a recessive mutation located on the X-chromosome males predominantly or exclusively affected mothers are carriers no male-to-male transmission some cases due to appearance of a new mutation in the family Examples: Duchenne muscu

42、lar dystrophy(DMD), color blindness, hemophilia A, glucose-6-phosphate dehydrogenase (G6PD) deficiency,XR,XR,Hemizygote: no corresponding loci on the Y chromosome, only one allele of each X chromosome locus.,XR,Duchenne Muscular Dystrophy (DMD)(Also known as Pseudohypertrophic),Definition One of nin

43、e types of muscular dystrophy, a group of genetic, degenerative diseases primarily affecting voluntary muscles. Cause An absence of dystrophin, a protein that helps keep muscle cells intact. Onset Early childhood - about 2 to 6 years. Symptoms Generalized weakness and muscle wasting first affecting

44、the musclesof the hips, pelvic area, thighs and shoulders. Calves are often enlarged. Progression DMD eventually affects all voluntary muscles, and the heart and breathing muscles. Survival is rare beyond the early 30s. A less severe variant is Becker muscular dystrophy. Inheritance XR. DMD primaril

45、y affects boys (1/3500 world-wide), who inherit the disease through their mothers. Women can be carriers of DMD but usually exhibit no symptoms.,DMD,DMD: Gowers maneuver,Genetics of DMD,occurring in about 1 in 3500 males, onset in early childhood, death by 3rd decade male births; X-linked recessive,

46、 lethal in males 1/3 of patients are new mutants; 2/3 have carrier mothers dystrophin, Xp21, Extremely large gene (more than 2000 kb), 79 exons. High mutation rate, probably due to large size of gene, 60% to 65% of the mutations are deletions, and about 6% are duplications , Allelic mutations in the

47、 same gene cause a milder disorder, Becker muscular dystrophy.,DMD (OMIM 310200): Xp21.2, 79 Exons, 2.4 mb,Other Examples of XR,Hemophilia A: a classical example anti Hemophilia factor deficiency. Glucose-6-Phosphate dehydrogenase deficiency (G6PD): G6PD is in the hexose monophosphate pathway, the o

48、nly NADPH-generation process in mature red cells, which lack the citric acid cycle. For this reason G6PD deficiency has adverse physiologic effects. Deficiency of the red cell enzyme, in various forms, is the basis of favism, primaquine sensitivity and some other drug-sensitive hemolytic anemias, an

49、emia and jaundice in the newborn, and chronic nonspherocytic hemolytic anemia Red- green color blindness: Color blindness afflicts 8% of males and 0.04 % of human females.,X-linked dominant(XD),XD,XD, due to a dominant mutation located on the X-chromosome males and females usually equally affected n

50、o male-to-male transmission; all daughters of an affected father are affected Examples: hypophosphatemic rickets, incontinentia pigmenti,XD,Examples of XD Disorders,Vitamin D-resistant rickets: There were no instances of male-to-male transmission of either bone disease or hypophosphatemia, and all d

51、aughters of hypophosphatemic males were themselves hypophosphatemic. Affected persons show a reduction in renal phosphate Tm to about 50% of normal. Males and females are not significantly different in this respect. caused by mutation in the phosphate-regulating endopeptidase gene (PHEX).,Vitamin D-

52、resistant rickets:Xp22.2-p22.1,Y-linked,Haired ears,Y-linked Disorders,they are always passed from father to son, and they never appear in females SRY(sex-determining region Y) : Analysis of such individuals has revealed some of the molecules involved in sex determination, including one called SRY,

53、which is important for testis formation. The testis-determining factor (TDF), formed under the influence of the SRY gene, induces the development of the fetal testis from an undifferentiated gonad.,Factors affecting pedigree patterns,Onset age Pleiotropy: multiple effects of a single gene (one gene,

54、 more than one effect ) Genetic heterogeneity Expressivity and penetrance Coefficient of relationship and consanguineous marriage Sex-limited phenotypes and sex-influenced phenotypes genomic imprinting Anticipation X inactivation, ,Pleiotropy,multiple effects of a single gene (one gene, more than on

55、e effect ) E.g.: Marfan syndrome (FBN1 gene),Genetic Heterogeneity,The phenomenon that a disorder can be caused by different allelic or non-allelic mutations. Locus heterogeneity Allelic heterogeneity Phenotypic (Clinical) heterogeneity,Genetic Heterogeneity,Allelic heterogeneity: In a population, t

56、here may be a number of different mutant alleles at a single locus. In an individual, the same or similar phenotypes may be caused by different mutant alleles rather than by identical alleles at the locus. E.g.: nearly 1400 different mutations have been found worldwide in the CFTR among patients with cystic fibrosis (CF).,Genetic Heterogeneity,Locus heterogeneity: The production of identical phenotypes by mutations at two or more different loci. E.g.: Osteogenesis Imperfecta (OI) or Brittle bone disease: Cs 7