單基因遺傳病高級(jí)遺傳

1、單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 單基因遺傳病單基因遺傳病 Single gene disorders Monogenic disorders 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Etiology of diseases. For any condition the overall balance of genetic and environmental determinants can be represented by a point somewhere within the triangle. Classification of Genetic Disorders Sing

2、le gene disorders are caused by defects in one particular gene, and often have simple and predictable inheritance patterns. They affect about 1 per cent of the population as a whole. Epigenetic modifications？ Other reasons? 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Multifactorial (common) Variants in genes causing alter

3、ation of function “Environmental” influences act on a genetic predisposition to produce a liability to a disease. One or more organ system affected. Person affected if liability above a threshold. Single gene (1% liveborn) Mutations in single genes (often causing loss of function) Dominant/recessive

4、 pedigree patterns (Mendelian inheritance). Can affect structural proteins, enzymes, receptors, transcription factors. Chromosomal (0.6% liveborn) Thousands of genes may be involved. Multiple organ systems affected at multiple stages in gestation. Usually de novo (trisomies, deletions, duplications)

5、 but can be inherited (translocations). Classification of genetic disorders + environment MaleMale Mitochondrial Somatic mutations (cancer) 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Single gene disorders:Single gene disorders: disorders in which inheritance is due to a single mutant disorders in which inheritance is due

6、 to a single mutant genegene Mendelian inheritanceMendelian inheritance Genes are units of heredity, based in DNAGenes are units of heredity, based in DNA Phenotype (physical or functional abnormalities)Phenotype (physical or functional abnormalities) Genotype (DNA change) Genotype (DNA change) 4. A

7、utosomal vs X-linked4. Autosomal vs X-linked determined by whether the responsible gene is determined by whether the responsible gene is carried on one of the autosomal chromosomes carried on one of the autosomal chromosomes or on the X chromosome or on the X chromosome 5. Dominant vs Recessive , ba

8、sed on phenotypic 5. Dominant vs Recessive , based on phenotypic expression expression 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Recessive Homozygotes with two copies of the altered gene are affected Dominant Heterozygotes with one copy of the altered gene are affected X-linked recessive Males with one copy of the alter

9、ed gene on the X-chromosome are affected MaleMale 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Single gene disorders - High risks to relatives - Dominant/recessive pedigree patterns - Some isolated cases due to new dominant mutations - Structural proteins, enzymes, receptors, transcription factors I:1I:2 II:1II:2II:3II:5II

10、:6II:8 III:1III:2 IV:1 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Characteristics of single gene inheritanceCharacteristics of single gene inheritance Autosomal DominantAutosomal Dominant vertical (successive), risk of affected offspring 50% (both sex) vertical (successive), risk of affected offsprin

11、g 50% (both sex) Autosomal RecessiveAutosomal Recessive horizontal, multiple sibs affected, usually one generation, consanguinity (+) horizontal, multiple sibs affected, usually one generation, consanguinity (+) risk of affected offspring 25%, carrier 50% risk of affected offspring 25%, carrier 50%

12、X-linked DominantX-linked Dominant daughters of affected males (+), sons of affected males (-), daughters of affected males (+), sons of affected males (-), affected females transmit the disorder to offspring of both sexes, affected females transmit the disorder to offspring of both sexes, risk of a

13、ffected offspring 50%, risk of affected offspring 50%, but twice as many affected females as affected males (no male to male) but twice as many affected females as affected males (no male to male) X-linked RecessiveX-linked Recessive males through carrier women, males affected almost exclusively, ma

14、les through carrier women, males affected almost exclusively, females affected only when affected father and carrier mother or with females affected only when affected father and carrier mother or with skewed X-inactivation skewed X-inactivation Y-linked Y-linked males affectedmales affected 單基因遺傳病高

15、級(jí)遺傳單基因遺傳病高級(jí)遺傳 Characteristics of Autosomal Dominant inheritance 1. The phenotype usually appears in every generation, each affected person having an affected parent Exceptions : (1)fresh mutation (2)the disorder is not expressed or is expressed only subtly in a person who has inherited the responsib

16、le gene. 2. Any child of an affected parent has a 50 percent risk of inheriting the trait 3. both males and females are affected in a 1 : 1 ratio 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Autosomal dominance inheritance (AD) Pedigree showing typical inheritance of a form of progressive sensorineural deafness (DFNA1) inh

17、erited as an autosomal dominant trait 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Characteristics of Autosomal Recessive Inheritance 1. An autosomal Recessive phenotype, typically is seen only in the sibship of the proband, not in parents, offspring, or other relatives. 2. both sexes are affected with equal frequency at a

18、 ratio of 1:1 3. Parents of an affected child are asymptomatic carriers of mutant alleles. heterozygous parents have a risk of 25% of affected offspring 4. The parents of the affected person may in some cases be consanguineous. This is especially likely if the mutant gene is rare in the population.

19、單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Autosomal Recessive Inheritance (AR) 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Characteristics of X-linked Dominant Inheritance 1. The incidence of the trait is much higher in females than in males (about twice) ,but affected females typically have milder (variable) expression of the phenotype. 2. A

20、ffected males with normal mates have normal sons and Affected daughters. 3. Both male and female offspring of Affected female have a 50 percent risk of inheriting the phenotype. 4.The pedigree pattern is the same as autosomal dominant inheritance. 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 X-linked Dominant Inheritance (

21、XD) 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Characteristics of X-Linked Recessive Inheritance The incidence of the trait is much higher in males than in females. The gene is ordinarily never transmitted directly from father to son (male-to-male), but it is transmitted by an affected male to all his daughters . A carri

22、er Female for an X-chromosomal mutation has a risk of 50% For an affected son. The gene may be transmitted through a series of carrier females; affected males inherit the mutant allele from the mother only 1. Heterozygous females are usually unaffected, but some may express the condition with variab

23、le severity as determined by the pattern of X inactivation 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 X-linked Recessive Inheritance (XR) 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 mutant allele X 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Y-linked inheritance 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Single gene disordersSingle gene disorders Huntington DiseaseHuntington Disease Myot

24、onic DystrophyMyotonic Dystrophy Hereditary Motor Sensory Neuropathy (HMSN)Hereditary Motor Sensory Neuropathy (HMSN) NeurofibromatosisNeurofibromatosis Marfan syndromeMarfan syndrome Cystic FibrosisCystic Fibrosis Spinal Muscular Atrophy (SMA)Spinal Muscular Atrophy (SMA) Duchenne Muscular Dystroph

25、yDuchenne Muscular Dystrophy 1.1. HemophiliaHemophilia 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Somatic mosaicism and single gene disorders 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Mosaicism: refers to a mixture of cells of different genetic composition in one individual. When the genotype of one zygote is altered by chromosomal mis- segr

26、egation or DNA mutation in a detectable number of cells, it is usually called mosaicism. Depending on the disorder and the class of mutation, in genes for which there are sufficient numbers of patients studied, 620% of cases are due to somatic mutation. The classes of mutation: base pair changes, in

27、sertions/deletion (indels), short tandem repeat mutations, copy number variants (CNVs), transposon-mediated mutations. 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Examples of confirmed somatic mosaicism Neurofibromatosis 1 and 2 McCune-Albright syndrome Paroxysmal nocturnal hemoglobinuria (PNH) and other disorders detecta

28、ble in separated blood cells Incontinentia pigmenti in males and other dermal and retinal examples of somatic mosaicism Somatic mosaicism in the heart and kidney Mutations in GJA5 in the cardiac DNA of patients with atrial fibrillation Alports syndrome in kidney Somatic mosaicism of the neuromuscula

29、r system X-linked Periventricular heterotopia Subcortical band heterotopia Somatic mosaicism in dysmorphic syndromes Townes-Brocks syndrome Camptomelic Dysplasia 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Combined germ-line and somatic mosaicism Mutation Research 705 (2010) 96106 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Paternal Age Effect

30、(PAE) and single gene disorders There are certain de novo germline mutations associated with genetic disorders whose mutation rates per generation are orders of magnitude higher than the genome average. Moreover, these mutations occur exclusively in the male germ line and older men have a higher pro

31、bability of having an affected child than younger ones. The classic example of a genetic disorder exhibiting a PAE is achondroplasia, caused predominantly by a single-nucleotide substitution (c.1138GA) in FGFR3. Possible explanation: Mutant spermatogonial stem cells have a proliferative advantage ov

32、er unmutated cells. Human Molecular Genetics, 2013, Vol. 22, No. 20 41174126 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 如何確定所研究的疾病是單基因??？如何確定所研究的疾病是單基因病？ 確認(rèn)方法主要有以下兩種：確認(rèn)方法主要有以下兩種： 1) 參考參考OMIM(Online Mendelian Inheritance in Man)數(shù)據(jù)庫，根據(jù)疾病數(shù)據(jù)庫，根據(jù)疾病 的表型或者臨床癥狀等確定是否屬于的表型或者臨床癥狀等確定是否屬于OMIM收

33、錄的單基因病。收錄的單基因病。 OMIM除了簡(jiǎn)略描述各種疾病的臨床特征、診斷、鑒別診斷、治療與預(yù)防除了簡(jiǎn)略描述各種疾病的臨床特征、診斷、鑒別診斷、治療與預(yù)防 外，還提供已知相關(guān)致病基因的連鎖關(guān)系、染色體定位、組成結(jié)構(gòu)和功外，還提供已知相關(guān)致病基因的連鎖關(guān)系、染色體定位、組成結(jié)構(gòu)和功 能、動(dòng)物模型等資料，并附有經(jīng)縝密篩選的相關(guān)參考文獻(xiàn)。能、動(dòng)物模型等資料，并附有經(jīng)縝密篩選的相關(guān)參考文獻(xiàn)。 網(wǎng)址為：網(wǎng)址為： 2) 繪制疾病的遺傳系譜圖，通過系譜圖分析其遺傳方式來判斷是否屬于繪制疾病的遺傳系譜圖，通過系譜圖分析其遺傳方式來判斷是否屬于 孟德爾遺傳病。孟德爾遺傳病。 系譜分析法是研究人類遺傳規(guī)律的重要

34、方法。在臨床上，常用系譜分析系譜分析法是研究人類遺傳規(guī)律的重要方法。在臨床上，常用系譜分析 法來判斷某種疾病的遺傳方式。系譜圖就是從先證者（法來判斷某種疾病的遺傳方式。系譜圖就是從先證者（proband）（家）（家 系中第一個(gè)被醫(yī)生確診的某遺傳病的患者，或者具有某種性狀的成員）系中第一個(gè)被醫(yī)生確診的某遺傳病的患者，或者具有某種性狀的成員） 入手，追溯調(diào)查其所有家庭成員的數(shù)目、親屬關(guān)系、某種遺傳病（或性入手，追溯調(diào)查其所有家庭成員的數(shù)目、親屬關(guān)系、某種遺傳?。ɑ蛐?狀）的分布等資料，按照一定格式繪制而成的圖解。狀）的分布等資料，按照一定格式繪制而成的圖解。 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺

35、傳 單基因病研究舉例及進(jìn)展單基因病研究舉例及進(jìn)展 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Rieger 綜合征(#MIM 180500)致病 基因PITX2的研究 Rieger 綜合征是Axenfeld-Rieger癥候群中最為嚴(yán)重的一 型 典型臨床表現(xiàn)： 眼前節(jié)發(fā)育不良，繼發(fā)青光眼 口頜發(fā)育異常： 先天多數(shù)牙缺失，過小牙，畸形牙 面中部發(fā)育不足，下頜前突等 臍殘斷回縮異常 遺傳方式：常染色體顯性遺傳，發(fā)生率約為1:200,000 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 臨床資料： 家系家系I I 先證者先證者 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Rieger綜合征相關(guān)基因和染色體區(qū)

36、域 PITX2 4q25 FOXC1 6p25 PAX6 11p13 13q14 All these Rieger-syndrome-associated genesencode transcription factors and have been shown to play important roles in embryonic development 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 測(cè) 序 結(jié) 果 Wild type 1-III:4 cloned1-III:4 uncloned 家系中的每位患者均存在PITX2基因第5 外顯子第717-720位ACTT四個(gè)堿基的雜 合缺失,導(dǎo)

37、致該基因的讀碼框移位,蛋白 質(zhì)大段功能域缺失,而家系中正常人不存 在此突變。 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 PITX2基因的特征 1996年定位克隆得到同源盒(homeobox) 基因PITX2， 編碼一種轉(zhuǎn)錄因子，屬于paired-bicoid基因家族， 在發(fā)育中高度保守，cDNA編碼區(qū)與小鼠的同源基 因91相同，蛋白質(zhì)的homeobox區(qū)100相同。 Paired-bicoid 的標(biāo)志是在同源結(jié)構(gòu)域(homeodomain) 第3螺旋50位有一賴氨酸殘基，這一殘基識(shí)別 TAAT盒后的CC序列。 小鼠Pitx2參與牙胚的定位，在牙齒發(fā)育的較早階 段表達(dá)于口腔上皮組織。Pitx2-

38、/- 的小鼠牙胚的發(fā) 育停止在蕾狀期。Pitx2還是心臟形態(tài)，上下頜骨 的前突，垂體發(fā)育所必需的。 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 PITX2 基因結(jié)構(gòu)圖 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 PITX2的重要功能域 PITX2基因的各種變異剪切體均含相同的 homeobox結(jié)構(gòu)域(HD)和C末端，但是N端 由不同的外顯子組成。 對(duì)PITX2分子C端功能的研究提示C端能 抑制DNA的結(jié)合從而為PITX2與協(xié)同因 子Pit-1作用創(chuàng)造條件。 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 PITX2突變譜的總結(jié) 15/23的突變發(fā)生在HD，7/23的突變發(fā)生 在HD的3編碼區(qū)。 圖中矩形

39、表示PITX2基因的外顯子，標(biāo)出了翻譯的起始（ATG）及終止 （TGA）位點(diǎn)。矩形中黑色的區(qū)域表示基因的Homeobox結(jié)構(gòu)域。圖中的 紅色星形、三角形、橢圓、圓形、箭頭依次表示不同的突變類型：剪切位 點(diǎn)突變、缺失突變、點(diǎn)突變、無義突變及插入突變。 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 PITX2突變功能研究 T68P位于HD第2個(gè)螺旋，該突變不改變蛋白質(zhì)對(duì)DNA 結(jié)合功能，但是使之失去調(diào)節(jié)基因轉(zhuǎn)錄的功能； L54Q位于HD的第1個(gè)螺旋，該突變使蛋白質(zhì)的穩(wěn)定性 喪失； K88E恰改變HD的第50位賴氨酸，不僅使蛋白質(zhì)喪失功 能，并且抑制野生型蛋白正常功能的行使； V45L位于HD的第1個(gè)螺

40、旋，該突變僅輕微降低DNA結(jié) 合活性，但是能夠大幅上調(diào)突變蛋白的轉(zhuǎn)錄活性。 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 PITX2突變類型與臨床表型的關(guān)系 不同類型的突變?cè)谂R床表型上存在差異。 Kozlowski等針對(duì)與不同臨床表型相關(guān)的5種 PITX2突變的功能研究表明，當(dāng)突變蛋白還擁 有部分功能時(shí)臨床的表型也較輕。 Espinoza等的實(shí)驗(yàn)也證實(shí)沒有牙齒異常表型的 突變R84W與PITX2調(diào)控基因Dlx2啟動(dòng)子的結(jié) 合能力與野生型相似，而含有所有臨床表型的 突變T68P則無法調(diào)節(jié)Dlx2的表達(dá)。 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 本研究中本研究中PITX2PITX2基因突變示意圖基因

41、突變示意圖 1 38 98 228 248 271 NC OARHD 野生型野生型 突變型突變型 1 44 82 NC ACTT Del 突變位于突變位于HDHD的起始部位，移除大段重要功能域，所引起的臨床表型，特別是的起始部位，移除大段重要功能域，所引起的臨床表型，特別是 牙齒的缺失是目前所有報(bào)道中最嚴(yán)重的牙齒的缺失是目前所有報(bào)道中最嚴(yán)重的 Novel Identification of a Four-base-pair Deletion Mutation in PITX2 in a Rieger Syndrome Family J Dent Res 82(12):1008-1012, 20

42、03 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 幾種特殊的突變類型 5調(diào)控區(qū)的突變 三核苷酸重復(fù)次數(shù)突變 與miRNA相關(guān)的突變 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 . Mutations in 5 regulatory region Selective Tooth Agenesis (STHAG), is the common generalized term used to describe congenitally missing teeth and is one of the most frequent developmental anomalies in humans. Gen

43、etic linkage studies on non-syndromic hypodontia have so far identified four genes underlying this condition: MSX1 ,PAX9,WNT10A and AXIN2 STHAG3 (OMIM #604625) is caused by heterozygous mutation in the PAX9 gene on chr14q12-13,which codes a transcription factor, and essential for the switch in odont

44、ogenic potential from the epithelium to the mesenchyme, are expressed in the dental mesenchyme at the initiation stage of tooth development 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 A family with Hypodontia 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Pedigree of family DEN29 with haplotypes for a SNP within (rs28933972) and microsatellite mar

45、kers (D14SA1462,D14S1463, D14S1464) near the PAX9 locus. The shaded haplotype is that segregating with the hypodontia phenotype. 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 A novel g.-1258GA mutation in a conserved putative regulatory element of PAX9 is associated with autosomal dominant molar hypodontia Clin Genet 2011:

46、80: 26572 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Multiple-species comparison of a 60 bp segment bearing the g.-1258GA variant identified by the arrow 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Microsatellite-expansion diseases a class of neurological and neuromuscular disorders caused by the expansion of short stretches of repetitive DNA

47、(e.g. GGGGCC, CAG, CTG . . .) within the human genome. a kind of mutation where microsatellite repeats in certain genes exceeding the normal, stable, threshold, which differs per gene. 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Nature Reviews Genetics 2010 Vol 11 786-99 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Huntington Disease (HD) Clinic

48、al Classification Movement/Cognitive/Psychiatric disorder Mean onset age 35-55 years. Prevalence Incidence 1 in 10,000. Genetic Testing Diagnostic Presymptomatic counselling protocol. 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Huntington Disease (HD) Physical features: - involuntary movements - weight loss - abnormal gai

49、t - speech DFNA50 mapped the phenotype to chromosome 7q32, caused by mutations in a microRNA, miR-96 This was the first study to implicate a miRNA in a mendelian disorder Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss. Nature Genet. 41: 609-613

50、, 2009 miRNA as a candidate gene of the disease 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Sequence analysis excluded UBE2H, SMO, ATP6V1F,CALU, CCDC136, TSPAN33, KLHDC10, C7ORF68, FLNC, IMPDH1 and MIR129-1. A set of three genes encoding miRNAs (MIR96, MIR182 and MIR183) was annotated within the interval. They are transcr

51、ibed as a single polycistronic transcript and were reported to be expressed in the inner ear 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Mutations in the seed region of MIR96 cause DFNA50 hearing loss. (a) Pedigrees of the Spanish families (family 1, top; 2, bottom) segregating DFNA50 hearing loss. (b) Electropherograms d

52、epict the 23-nt mature sequence of human miR-96. The nucleotides corresponding to the seed region are boxed. 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Predicted secondary structure and processing of the wild-type and mutant forms of miR96. 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Downregulation of predicted primary targets is impaired by t

53、he miR-96 (+13GA) and (+14CA) mutations. 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Lewis MA, Quint E, Glazier AM et al. An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice. Nat Genet 2009: 41: 614618. A mouse mutant presented a phenotype similar to the human disease, which carries a (AT) b

54、ase substitution in the seed sequence of miR-96. 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Sequence Variants in SLITRK1 Are Associated with Tourettes Syndrome Science 2005：310, 317-320 The single-base change maps to the 3UTR of the SLITRK1 transcript and corresponds to a highly conserved nucleotide within the predicted

55、binding site for the human miRNA hsa-miR-189 Mutation or SNP (also referred to as miRSNP) is located in the miRNA-binding site, or nearby 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Mutations are located in a predicted target site for miR-140 and in a predicted target site for miR-691 within the 3UTR

56、of REEP1. 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am J Hum Genet 2006: 79: 365369. 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Beetz C, Schule R, Deconinck T et al. REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic

57、paraplegia type 31. Brain 2008: 131: 10781086 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 The complexity of modifying factors for phenotypes of single gene disorders cis- and trans-acting factors epigenetic factors proteins belonging to the same pathway or network proteins involved in stand-alone pathways but converging o

58、n a common final pathway or ending in the same biological function extrinsic non-genetic or environmental factors. 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 同一信號(hào)轉(zhuǎn)導(dǎo)通路的不同基因發(fā)生突變的同一信號(hào)轉(zhuǎn)導(dǎo)通路的不同基因發(fā)生突變的 同類疾病同類疾病 The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation Current Opinion in Genetics & Development 2

59、009, 19:230236 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Ras/mitogen-activated protein kinase (MAPK) pathway Plays an essential role in the control of the cell cycle and differentiation Its dysregulation has profound developmental consequences. 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 Each RASopathies each exhibit uniq

60、ue phenotypic features Many share characteristic overlapping features Craniofacial dysmorphology Cardiac malformations Cutaneous, musculoskeletal and ocular abnormalities, Varying degrees of neurocognitive impairment In some syndromes, an increased risk of developing cancer. 單基因遺傳病高級(jí)遺傳單基因遺傳病高級(jí)遺傳 單基因