遗传学英文课件：Monogenic disorder (2)

1、Suggested Readings,Turnpenny P, Ellard S. Emerys elements of medical genetics: With Student Consult Access. 14th edition. Churchill Livingstone, 2012 Jorde LB, et al. Medical genetics. 4th ed. Mosby, 2010. Passarge E. Color atlas of genetics. 4th ed. Thieme Medical Publishers, 2013 Scriver CR, et al

2、. The metabolic and molecular bases of inherited disease.8th ed. McGraw-Hill Companies, 2001 Rimoin DL , et al. Emery and Rimoins Principles and Practice of Medical Genetics. 5th ed. Churchill Livingstone, 2006 Tobias ES, et al. Essential Medical Genetics. 6th ed. Wiley-Blackwell, 2011 Schaaf CP, et

3、 al. Human Genetics: From Molecule to Medicine. LWW, 2012 Young ID. Medical Genetics. OUP, 2010 Strachan T, Read A. Human molecular genetics. 4th ed. Garland Science, 2010 ,Top Journals of Molecular Medicine,CNS NEJM Lancet Nature Medicine Nature Genetics AJHG AJMG Nat. Rev. Genet. Annu. Rev. Genomi

4、cs Hum. Genet. Annu. Rev. Genet. Trends Mol Med Genome Res. Hum. Mol. Genet. Hum. Mutat. J. Med. Genet. Genetics in Medicine,Useful Internet,Information on any mendelian phenotype: Genome data: ; Information on proteins: Biome

5、dical literature: /entrez/ Human gene mutation database: Human disease genes list: http:/bioinfo.weizmann.ac.il/cards Genetic diagnosis: ,1966:MIM（McKusick VA, 1921-2008）,Last updated:7/31/2014. Numbers of reference: 88. Pubmed sear

6、ch references: 93564 !,Monogenic disorder(Patterns of single-gene disorder),ZHANG Xian-Ning, PhD Tel 88208367 Office: C303, Teaching Building 2014/09,Genotype: The combination of alleles that an individual possesses. Phenotype: The physical characteristics of a cell or organism as defin

7、ed 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 produce variation in inherited characteristics such as hair color or blood type. Pedigree: A simplified diagram of a familys genealogy that sho

8、ws 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 to the attention of an investigator is proband. Pedigree symbols,Symbols Commonly Used in Pedigree Charts,Proband（先证者）: III-5 Pedigree drawing s

9、oftware：Progeny, etc.,Major Patterns of Monogenic Inheritance,Patterns of autosomal dominant inheritance (AD) Patterns of autosomal recessive inheritance (AR) Patterns of X-linked dominant inheritance (XD) Patterns of X-linked recessive inheritance (XR) Patterns of Y-linked inheritance,Autosomal Dom

10、inant,AD,AD,AD,AD, requires mutation in only one allele to produce disease males and females equally affected family history usually positive, with affected members in each generation may show apparent generation skipping due to variable penetrance, variable expressivity, or appearance of a new muta

11、tion in the family Examples: Huntington disease, Marfan syndrome, neurofibromatosis, familial breast/ovarian cancer, myotonic dystrophy,AD,Huntington Disease (HD),A progressive disorder of motor, cognitive, and psychiatric disturbances. The mean age of onset is 35 to 44 years and the median survival

12、 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-causing allele.,HD case-Woody Guthrie(1912-1967),Huntington Disease (HD),Frequency estimated to be about 3-7/100 000 in populations of western E

13、uropean descent. AD, Homozygotes for HD appear to have a similar age of onset to heterozygotes, but may exhibit an accelerated rate of disease progression. The HD gene is the only gene associated with Huntington disease. A trinucleotide CAG repeat expansion in Exon 1 is the only mutation observed. A

14、nticipation:,Trinucleotide CAG repeat sizes in HD,Normal 26 Mutable 27-35 Reduced penetrance 36-39 Fully penetrance 40,Anticipation,the phenomenon in which increasing disease severity or decreasing age of onset is observed in successive generations, is known to occur in HD. occurs more commonly in p

15、aternal transmission of the mutated allele. The phenomenon of anticipation arises from instability of the CAG repeat during spermatogenesis. Large expansions (i.e., an increase in allele size 27 CAG repeats) occur almost exclusively through paternal transmission. Most often children with juvenile-on

16、set disease have inherited the expanded allele from their fathers.,4p16.3, mapped in 1983. HD gene, isolated in 1993 using haplotype analysis of linkage disequilibrium. Huntingtin, a protein of 3144 amino acids with a predicted molecular mass of 348 kd. The CAG repeat in the HD gene is translated in

17、to an uninterrupted stretch of glutamine residues that when expanded may have altered structural and biochemical properties.,Huntington Disease (HD),Mary (35 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

18、have a mutable normal allele when he was tested following diagnosis of his brother, Bart. All three siblings chose molecular genetic testing following genetic counseling and neurologic evaluation. All have normal neurologic examinations.,Clinical Case,What do these results mean?,Mary 38 CAG repeats,

19、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 normal allele. Expansions of 27-35 CAG repeats have never been associated with clinical symptoms of HD; however, his children are at some risk to

20、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 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 l

21、ife 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 in the reduced penetrance range or expand into the full penetrance range.,Mary (35 y.o.) 38 CAG repeats Reduced penetrance allele,Samuel,Alice,A

22、lice (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 individual lives a normal life span. Alices children are at 50% risk to inherit the full penetrance allele and therefore to develop HD.,Mary,Samue

23、l,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 (4p16.3) with RFLP linkage analysis. (Gusella et al.) Robertson:“The beginning of the end of dilemma?” (Nature) The HD gene, Huntingtin, was isolat

24、ed in 1993 after a decade of intense collaborative efforts among many laboratories from various countries and officially designated HD. (Gusella et al.) Little:“Huntingtons disease: The end of the beginning” (Nature),Locations of Repeats,Richards COL1A2, 7q22.1) -Locus heterogeneity,bone fragility r

25、educed life span short stature dentinogenesis hearing loss affects 1/10 000 individuals,OI type I,Blue sclerae Near normal height Fractures Hearing loss Dominant inheritance,OI type II,Severe bone compression Soft calvarium Blue sclerae Perinatal death New in family,OI type III,Very short Marked and

26、 progressivedeformity Blue or normal sclerae Dentinogenesis imperfecta Often non-ambulatory Often new in family,OI type IV,Normal sclerae Mild-moderate short stature Fractures Dentinogenesis imperfecta Bone deformity Dominant inheritance,AD null or structural mutations in type I collagen a chain gen

27、es lead to different types of OI dominant negative effect haploinsufficiency germline mosaicism,Genetic Basis of Osteogenesis Imperfecta,Classic Ehlers-Danlos syndrome(EDS),More than 70% have mutations in COL5A1 (9q34.2-q34.3) of which a third have premature termination codons Rare mutations in COL5

28、A2 (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 dislocation and child abuse. His past medical history was significant for child abuse, for which he was removed from his home on several occasi

29、ons. 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 joints 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 E

30、hlers-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,4.5-year-old boy,Unusual Features of Autosomal Dominant Inheritance,Reduced penetrance Variable expressivity High frequency of new mutations,Autos

31、omal Recessive(AR),AR,AR,AR,AR, requires mutation of both alleles to produce disease males and females equally affected higher frequency in consanguineous matings higher frequency of mutation carriers in particular ethnic groups family history often negative often associated with enzymatic defects c

32、ausing metabolic disorders Examples: sickle cell disease, phenylketonuria, cystic fibrosis, spinal muscular atrophy, Wilson disease,AR,AR,Develop in persons 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

33、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 which a defect (Glu6Val) in 146 AA -hemoglobin, the oxygen-carrying pigment in the blood, causes Hb aggregation and distortion (sickling) and loss

34、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 GAG GAG- -Pro Glu Glu-,6,Cystic Fibrosis ( CF ),Severe progressive disease of the bronchial system and gastrointestinal tract Disturbed function

35、 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 amino acids. AR Disease incidence approx. 1:2000 in Caucasian.,CFTR Gene,1st gene identified by positional cloning Identified by the research gr

36、oup 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: 1059-1065. - (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245: 1066-1073. - (1989)

37、Identification of the cystic fibrosis gene: genetic analysis. Science 245: 1073-1080.,CF,Other Examples of AR Disorders,Phenylketonuria ( PKU ): Gene locus (PAH) : 12q22-24. Disease incidence 1:16000, cirrhosis of liver, galactosuria and mental retardation. Mutations in the gene for phenylalanine hy

38、droxylase. Albinism: A pigmentless “white” phenotype, determined by a mutation in a gene coding for a pigment-synthesizing enzyme.,Spinal muscular atrophy (SMA) A disorder characterized by degeneration of lower motor neurons and occasionally bulbar motor neurons leading to progressive limb and trunk

39、 paralysis as well as muscular atrophy. It is a clinically and genetically heterogeneous group of neuromuscular diseases. It is the second most common lethal autosomal recessive disorder after cystic fibrosis in Caucasian populations with an overall incidence of 1 in 10000 live births and a carrier

40、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/After penicillamine therapy,X-linked Recessive (XR),XR,XR,XR,XR, due to a recessive mutation located on the X-chromosome males predominantly or

41、exclusively affected mothers are carriers no male-to-male transmission some cases due to appearance of a new mutation in the family Examples: Duchenne muscular dystrophy(DMD), color blindness, hemophilia A, glucose-6-phosphate dehydrogenase (G6PD) deficiency,XR,XR,Hemizygote: no corresponding loci o

42、n the Y chromosome, only one allele of each X chromosome locus.,XR,Duchenne Muscular Dystrophy (DMD)(Also known as Pseudohypertrophic),Definition One of nine types of muscular dystrophy, a group of genetic, degenerative diseases primarily affecting voluntary muscles. Cause An absence of dystrophin,

43、a protein that helps keep muscle cells intact. Onset Early childhood - about 2 to 6 years. Symptoms Generalized weakness and muscle wasting first affecting the musclesof the hips, pelvic area, thighs and shoulders. Calves are often enlarged. Progression DMD eventually affects all voluntary muscles,

44、and the heart and breathing muscles. Survival is rare beyond the early 30s. A less severe variant is Becker muscular dystrophy. Inheritance XR. DMD primarily affects boys (1/3500 world-wide), who inherit the disease through their mothers. Women can be carriers of DMD but usually exhibit no symptoms.

45、,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, 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.

46、 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 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

47、classical example anti Hemophilia factor deficiency. Glucose-6-Phosphate dehydrogenase deficiency (G6PD): G6PD is in the hexose monophosphate pathway, the only NADPH-generation process in mature red cells, which lack the citric acid cycle. For this reason G6PD deficiency has adverse physiologic effe

48、cts. Deficiency of the red cell enzyme, in various forms, is the basis of favism, primaquine sensitivity and some other drug-sensitive hemolytic anemias, anemia and jaundice in the newborn, and chronic nonspherocytic hemolytic anemia Red- green color blindness: Color blindness afflicts 8% of males a

49、nd 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 no male-to-male transmission; all daughters of an affected father are affected Examples: hypophosphatemic rickets, incontinentia pigmenti,XD,Exam

50、ples of XD Disorders,Vitamin D-resistant rickets: There were no instances of male-to-male transmission of either bone disease or hypophosphatemia, and all daughters of hypophosphatemic males were themselves hypophosphatemic. Affected persons show a reduction in renal phosphate Tm to about 50% of nor

51、mal. Males and females are not significantly different in this respect. caused by mutation in the phosphate-regulating endopeptidase gene (PHEX).,Vitamin D-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 femal

52、es SRY(sex-determining region Y) : Analysis of such individuals has revealed some of the molecules involved in sex determination, including one called SRY, which is important for testis formation. The testis-determining factor (TDF), formed under the influence of the SRY gene, induces the developmen

53、t of the fetal testis from an undifferentiated gonad.,Factors affecting pedigree patterns,Onset age Pleiotropy: multiple effects of a single gene (one gene, more than one effect ) Genetic heterogeneity Expressivity and penetrance Coefficient of relationship and consanguineous marriage Sex-limited ph

54、enotypes and sex-influenced phenotypes genomic imprinting Anticipation X inactivation, ,Pleiotropy,multiple effects of a single gene (one gene, more than one effect ) E.g.: Marfan syndrome (FBN1 gene),Genetic Heterogeneity,The phenomenon that a disorder can be caused by different allelic or non-alle

55、lic mutations. Locus heterogeneity Allelic heterogeneity Phenotypic (Clinical) heterogeneity,Genetic Heterogeneity,Allelic heterogeneity: In a population, there 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 Heterog