遗传学复习材料：遗传学突变及疾病汇总

1、Transcription factors (TFs)： Response elements: regulated in response to certain TFs Each TF has a specific binding sequence TFs have primary responsibility for recognizing promoter, binding to the RNA pol and positioning it correctly at the startpoint cis-acting elements in promoter Formation of pr

2、e-initiation complex Mutations突变A mutation is a structural change in genomic DNA sequence due to errors in DNA replication or repair. - Mutations may or may not result in an expressed phenotype.- Mutations that have no phenotype are called neutral mutations.- Mutations can alter RNA expression, proc

3、essing and/or stability.- Mutations can also affect protein expression, processing, stability.- Mutations can be inherited (genetic/germ line mutations) not inherited (somatic mutations)Structural classification of mutations1. Point mutations: change in one base pair of DNA.(1) silent mutations（neut

4、ral mutations）: changes in DNA which do not affect protein expression or function.(2) missense mutations: changes in DNA which lead to a change in an amino acid.(3) nonsense mutations: changes in DNA which generate a termination codon and thus stop translation.(4) Regulatory mutations: one which inv

5、olves the promoter or another regulatory sequence such as an enhancer, silencer, or locus control region.(5) RNA processing mutations: These affect the processing of the primary RNA transcript to form mRNA, either by altering normal RNA splicing or by preventing either normal 5-capping or 3-polyaden

6、ylation.2. Deletions and insertions: (1) small deletions and insertions: If the number of nucleotides deleted or inserted in an exon is not a multiple of three, then the sequence of codons, known as the reading frame, is disrupted. This is referred to as a frame-shift a truncated protein.(2) large d

7、eletions and insertions: These range in size from 20 bp to 10 Mb, beyond which they become visible using a light microscope and are classified as chromosome abnormalities.(3) unequal crossing-over: Crossing-over between misaligned closely adjacent sequences which show close homology results in the f

8、ormation of a deletion in one chromatid and a duplication in the other.(4) retrotransposition: Transposable elements, SINES and LINES, which have moved from an inert region of the genome to become inserted into an exon elsewhere.Polymorphisms（多态性） Mutations that are propagated and maintained in the

9、population at relatively high frequencies are called polymorphisms. Polymorphism is defined as the existence of two or more alleles, where the rare allele appears with a frequency greater than 1% in the population. Most mutations are quickly lost from population due to deleterious effects (natural s

10、election) or genetic drift (random fluctuations). Mutations may become polymorphisms due to selective advantage (heterozygotes for hemoglobin sickle cell mutation are more resistant to malaria) or genetic drift (founder effect, small group of individuals found a new population). Multiple functional

11、alleles at a frequency of >1% in a population A population may have extensive polymorphism at the level of genotype It may offer a diagnostic procedure for detecting the disease It may lead to isolation of the gene.疾病汇总：Chromosomal disorder1、Typical Turners syndrome：45，X (the only monosomy can be

12、 survived)n Short staturen Gonadal dysgenesis: steak gonads n Unusual faces, webbed neck, low posterior hairline, broad chest with widely spaced nipples n 先天性卵巢发育不全，为女性缺少一条X染色体所致的身材矮小、原发性闭经、颈蹼、肘外翻等异常。本型发病率远比上一型低，约占女性智力缺陷的0.64%，其临床特点为患者外貌女性，身体较矮，第二特征发育不良，卵巢缺如，无生育能力。部分患者智力轻度低下。有的患者伴有心、肾、骨骼等先天畸形。2、Down

13、s syndrome: Trisomy 21 (most common trisomy 1:800 in new born)n Eyes with brushfield spot n Flat nosal bridgen Low set earn Open mouth with protruding tonguen Short and broad hand with a single transverse palmar creaseRelated with advanced maternal age1.患儿具明显的特殊面容体征，如眼距宽，鼻根低平，眼裂小，眼外侧上斜，有内眦赘皮，外耳小，舌胖，

14、常伸出口外，流涎多。身材矮小，头围小于正常，头前、后径短，枕部平呈扁头。颈短、皮肤宽松。骨龄常落后于年龄，出牙延迟且常错位。头发细软而较少。前囟闭合晚，顶枕中线可有第三囟门。四肢短，由于韧带松弛，关节可过度弯曲，手指粗短，小指中节骨发育不良使小指向内弯曲，指骨短，手掌三叉点向远端移位，常见通贯掌纹、草鞋足，拇趾球部约半数患儿呈弓形皮纹。2.常呈现嗜睡和喂养困难，其智能低下表现随年龄增长而逐渐明显，智商2550，动作发育和性发育都延迟。3.男性唐氏婴儿长大至青春期，也不会有生育能力。而女性唐氏婴儿长大后有月经，并且有可能生育。4.患儿常伴有先天性心脏病等其他畸形，因免疫功能低下，易患各种感染，白

15、血病的发生率比一般增高1030倍。如存活至成人期，则常在30岁以后即出现老年性痴呆症状。3、Edwards syndrome: Trisomy 18n 1:7500 in liveborn and more common in abortion and stillbirthn Sever mental retardation and multiple structural anomalies异常成长速度异常延迟，发育方面的延迟，智能障碍男性生殖系统睾丸部分隐藏于腹腔之内，如此会导致不育后部头颅突出小型头颅畸形耳朵下垂、变形异常的小颚畸形小型口腔兔唇颚裂鼻尖朝上眼睑出现皱褶（裂缝）双眼之间存在较

16、阔的空间上眼睑下垂手指重叠、扭曲拇指发育不全（或者完全消失）指甲发育不全于第二脚趾与第三脚趾之间出现蹼状物足部向内弯曲臀部运动幅度受限制、小型盆骨胸骨过短4、Pataus syndrome: Trisomy 13n 1:20,000 in liveborn and more common in abortion and stillbirthn Sever structural anomalies lead to death in one month5、XXY, Klinefelters syndromen 1:1,000 in male livebornn Hypogonadism（生殖官能不

17、良） and Infertility（不孕）:1. Tall stature2. Long limbs3. Small genitalia（生殖器小）4. Gynecomastia（男子女性型乳房）6、47, XYY syndromen 1:1,000 in male live birthn Normal intelligence and normal appearance but:1. Educational problem: language delays and spelling difficulties2. Behavioral problems: attention deficits

18、, hyperactivity and impulsiveness3. Fertility problem: increase risk of chromosomal abnormal child7、47, XXX syndromen 1:1,000 in Female live birthn Normal intelligence and normal appearancen A significant deficit in performance on IQ testsn 70 % with some learning problemsn Infertility: 50%8、8、Cri D

19、u Chat (5p-) syndrome n Deletion: 5p15n Crying sounds like a newing catn Typical features: hypertelorism（器官过距）, epicanthus（内眦赘皮） and retrognathia（颌后缩），智力低下X chromosome inactivation and XISTn Gene dosage compensation is achieved in all persons with two or more X chromosomes in their genetic constitut

20、ion by partial inactivation of all X chromosomes except one. n The process is controlled by XIST (X inactive specific transcripts) gene in Xq13.2, which encodes a large RNA that appears to "coat" the X chromosome and facilitate inactivation of genes on the X chromosome.证实：n During the late

21、 blastocyst stage, all X chromosomes except one undergo heterochromatinization and form X chromatin bodies in each cell.n The balance of gene dosage on X chromosome is achieved. 结论：The explanation of various kinds of X polysomies in live-birth. Chromosome small deletion syndrome9、Parader-Willi Syndr

22、omes (PWS)n Excessive eating and Obesityn Small hands, feet and short staturen Hypogonadism性腺机能减退n Mental retardation智力缺陷10、Angelman Syndromes (AS)n Unusual facial appearance,n Short staturen Spasticity, Seizure痉挛n mental retardation11、DiGeorge (velo-cardio-facial, 22q11.2 deletion) syndrome软腭-心-面综合

23、症 Congenital heart disease (particularly conotruncal malformations椎干畸形) Palatal（腭） abnormalities especially velopharyngeal insufficiency (VPI) Hypocalcemia低血钙 Immune deficiency免疫缺陷 Learning difficulties12、Williams syndrome：Deletion of 7q11.23 or elastin gene （弹性蛋白基因）n Characteristic dysmorphic facie

24、s, frequently referred to as elfin facies (100%)n Supravalvular aortic stenosis (80%)主动脉瓣狭窄n Variable mental retardation (75%)n Characteristic cognitive/behavioral profile (90%)13、Steroid（类固醇） Sulfatase（硫酸酯酶） Deficiency and X-Linked Ichthyosis（鱼鳞癣）：Deletion of Xp22.3 STSn X-linked ichthyosis showing

25、 thick, large, polygonal多边形, dark-brown scales （鳞癣）involving the extensor（伸肌）.n Steroid sulfatase deficiency during pregnancy in carrier females: Leads to an overall decrease in the levels of estrogen（雌性激素）14、Kallmann's syndrome：Deletion of Xp22.3 KALn Congenital reduced pituitary（脑垂体） gonadotro

26、pic（促性腺激素） activity with resulting association of hypogonadism（性腺机能减退）, eunuchoidism（类无睾症） and anosmia（嗅觉缺失）.AD Disorders15、Huntington chorea, 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

27、 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. Frequency estimated to be about 3-7/100000 in populations of western European descent. AD, Homozygotes for HD appear to have a similar age of ons

28、et 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 is the only mutation observed. Anticipation(遗传早现) the phenomenon in which increasing disease severity or decreasing a

29、ge 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 expansions (i.e., an increase in allele size >27

30、CAG repeats) occur almost exclusively through paternal transmission. Most often children with juvenile-onset disease have inherited the expanded allele from their fathers.16、Fragile X Syndrome脆性X染色体综合症 Macrocephaly 大头 Large ear with soft cartilage Normal life span CGG trinucleotide repeat17、Marfan S

31、yndrome蜘蛛脚样指趾 眼、骨骼、心血管三联病n Ocular眼Lens dislocation（晶状体脱位）about 70% by age 6-10 yearsn CardiovascularAortic dilatation（主动脉扩张）about 50% by age 10Aortic dissection（主动脉夹层）about 50% by age 48Mitral valve prolapse（二尖瓣脱垂）about 75% by age 12n Musculoskeletal肌肉骨骼Height/span and US/LS 75% by age 12 yearsPectu

32、s excavatum 漏斗胸(“hollow chest”), 75% by age 15 yearsn Dural ectasia硬脑膜扩张?100% by age 20 yearsn Family history60%-75% by age 10 years Frequency estimated to be about 1/15000 AD inheritance but about 25% represent new mutation。18、Osteogenesis Imperfecta (OI) 成骨发育不全a heterogeneous group of genetic diso

33、rders(COL1A1, 17q21.3-q22; COL1A2, 7q22.1) -Locus heterogeneity基因座异质性 bone fragility reduced life span short stature dentinogenesis imperfecta牙本质发育不全 hearing loss affects > 1/10 000 individuals（1）OI type I Blue sclerae蓝色巩膜 Near normal height Fractures Hearing loss Dominant inheritance（2）OI type I

34、I Severe bone compression Soft calvarium颅盖柔软 Blue sclerae Perinatal death围产死亡 New in family（3）OI type III Very short Marked and progressive deformity畸形 Blue or normal sclerae Dentinogenesis imperfecta 牙本质发育不全 Often non-ambulatory不能行走 Often new in family（4）OI type IV Normal sclerae Mild-moderate shor

35、t stature Fractures Dentinogenesis imperfecta Bone deformity Dominant inheritanceGenetic Basis of Osteogenesis Imperfecta AD null or structural mutations in type I collagen a chain genes lead to different types of OI dominant negative effect haploinsufficiency germline mosaicism19、Classical Ehlers-D

36、anlos syndrome(EDS)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 occasions. On examination he had marked scarring of his fore

37、head, 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 Ehlers-Danlos type I was made and he was returned to his

38、 home,where he once again suffered abuse at the hands of his mother and her boy friend.总结Unusual Features of Autosomal Dominant Inheritance Reduced penetrance Variable expressivity High frequency of new mutationsAR Disorders20、Sickle cell anemia lethal disease in which a defect (Glu6Val) in 146 AA -

39、hemoglobin, the oxygen-carrying pigment in the blood, causes Hb血红蛋白aggregation凝集 and distortion (sickling) and loss of red blood cells, producing damage to organs throughout the body 1st identified Hb disease 1/600 African Americans 21、Cystic Fibrosis ( CF ) 囊性纤维化 Severe progressive disease of the b

40、ronchial气管 system and gastrointestinal tract胃肠道 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 amino acids. AR Disease incidence approx. 1:2000 in Caucasian. 22、Phenylketonu

41、ria ( PKU ): Gene locus (PAH) : 12q22-24. Disease incidence 1:16000, cirrhosis of liver, galactosuria 半乳糖尿症and mental retardation. Mutations in the gene for phenylalanine hydroxylase. 苯丙氨酸羟化酶23、Albinism: A pigmentless “white” phenotype, determined by a mutation in a gene coding for a pigment-synthes

42、izing enzyme.色素合成酶24、Spinal muscular atrophy (SMA)A disorder characterized by degeneration of lower motor neurons下运动神经元坏死 and occasionally bulbar motor neurons延髓神经元 leading to progressive limb and trunk paralysis四肢和躯干无力 as well as muscular atrophy.肌肉萎缩 It is a clinically and genetically heterogeneou

43、s 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 frequency of approximately 1 in 50.25、Wilson disease: Cu toxicity, AR肝豆状核变性XR Disorders

44、25、Duchenne Muscular Dystrophy (DMD)假肥大性肌营养不良 Definition One of nine types of muscular dystrophy, a group of genetic, degenerative diseases primarily affecting voluntary muscles随意肌. Cause An absence of dystrophin抗肌萎缩蛋白, a protein that helps keep muscle cells intact. Onset Early childhood - about 2 t

45、o 6 years. Symptoms Generalized weakness and muscle wasting first affecting the muscles of the hips臀部, pelvic area盆腔, thighs大腿 and shoulders. Calves小腿 are often enlarged. Progression DMD eventually affects all voluntary muscles, and the heart and breathing muscles. Survival is rare beyond the early

46、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. 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 s