Sequence Analysis of the Human Genome Implications for the Understanding of Nervous System Function and Disease

BASIC SCIENCE SEMINARS IN NEUROLOGY

SECTION EDITOR: HASSAN M. FATHALLAH-SHAYKH, MD Sequence Analysis of the Human Genome Implications for the Understanding of Nervous System Function and Disease

Anibal Cravchik, MD, PhD; G. Subramanian, MD, PhD; Samuel Broder, MD; J. Craig Venter, PhD

he recent publication of the sequence of the human genome will accelerate the discovery of new genetic susceptibility factors for human disease, leading to the development of novel diagnostics and therapeutics. The exhaustive analysis of the human genome sequence will be the focus of the biomedical research community for many Tyears to come. In particular, comparative analysis of the available eukaryotic genome sequences is an important approach to further our understanding of gene structure, function, and evolution. Our initial analysis of the human genome sequence has revealed many interesting features that are relevant to nervous system function, evolution, and disease. We analyzed the prominent features of predicted human proteins involved in neuronal function and prepared a comparative analysis of 146 human genes that have alleles (or mutations) conferring susceptibility for 168 neurologic diseases. Arch Neurol. 2001;58:1772-1778

The recent publication of the sequence of to further our understanding of gene func- the human genome1,2 allows a compara- tion and evolution. Any such analysis must tive analysis of genes expressed in the ner- take into account that the human genome vous system and genes associated with is estimated to contain 26000 to 38000 neurologic disease. The nervous system in genes, the fruit fly genome contains about vertebrates exhibits a high degree of func- 14000 genes, and the nematode has about tional complexity, which is supported by 19000 genes. The expansion of gene fami- a comparatively large number of genes ex- lies in the human genome is not uniform, pressed in the nervous tissue. Many hu- but instead reflects the important roles of man neurologic diseases resulting from ge- developmental and cellular processes that netic mutations have been described. The are unique to vertebrates. human genes that confer susceptibility to neurologic diseases belong to many dif- COMPARATIVE GENOME ANALYSIS ferent families and have a large diversity of functions. Human genes that confer dis- An initial comparative analysis of the hu- ease risk are, of course, not “disease genes,” man genome with the fruit fly and nema- as they are sometimes referred to, be- tode genomes showed a marked expan- cause their primary function is certainly sion in the number of genes coding for not to cause disease. However, the obser- proteins involved in neural develop- vation that an alteration in a gene se- ment, function, and structure.1 This find- quence results in a detectable disease sug- ing correlates with, but does not com- gests that the gene product plays a critical pletely explain, the observation that the role for the survival of the whole organ- human nervous system has a much larger ism. We call such gene sequence alter- number of different neuronal cell types ations disease-predisposing alleles. than the fruit fly and nematode nervous The comparative analysis of the hu- systems.5 Such diversity in neuronal mor- man genome with the fruit fly and nema- phology reflects the variety and complex- tode genomes3,4 is an important approach ity of gene expression and regulation in the different neuronal cell types of the ver- From Celera Genomics, Rockville, Md. tebrate nervous system. Protein families

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 involved in nervous system func- 120 Nematode tion and development that are promi- Fruit Fly Human nently expanded in humans include 100 myelin-related proteins, proteins in-

volved in neuronal signaling (voltage- 80 gated ion channels and connexins),

and proteins involved in pathway 60 finding by axons and neuronal net- No. of Proteins work formation (cadherins, eph- 40 rins, semaphorins, neuropilins, and Figure 1 1,6,7 plexins) ( ). Of equal in- 20 terest is the expansion of proteins involved in apoptotic regulation8; the 0 process of programmed cell death or Actins Ephrins Plexins apoptosis is likely to play an impor- MAP2/tau Cadherins Connexins Neuropilins Semaphorins tant role in neurodegenerative dis- Voltage-GatedVoltage-GatedVoltage-GatedMyelin-Related 9 Calcium Channels Sodium Channels eases. Also expanded in humans are Potassium Channels neuronal cytoskeleton protein families such as actins and microtubule- Figure 1. Expansions in human protein families involved in neural function, structure, and development. Number of proteins in selected families in the human, fruit fly, and nematode are compared (data from associated proteins (MAPs) of the Venter et al1). MAP2/tau family (Figure 1). Sev- eral of the proteins involved in neu-

ronal communication are multido- Protein Domain Architecture Biological or Clinical Relevance main proteins (a protein domain is Channel-associated protein of synapse 110 (Chapsyn-110): The described as a region on a protein that P P P human genome shows an expansion of the family of synaptic shows structural, functional, and evo- D D D SH3 GuKc MAGUK (membrane-associated guanylate kinase) proteins. These Z Z Z proteins interact with and regulate neuronal specific ion channels lutionary conservation). The obser- (NMDA receptors and potassium ion channels). vation of “domain shuffling” (whereby new multidomain protein P P P P Neuronal interleukin 16: A dual-function PDZ domain protein in the D D IL D D nervous system that serves as a secreted signaling molecule as well architectures are built by shuffling or Z Z Z Z as a scaffolding protein. adding different evolutionarily conserved protein domains) is a promi- B B B L L L L L Neuronal apoptosis inhibitory protein: Prevents motor neuron I I I NACHT R R R R R apoptosis induced by a variety of signals. Mutated or deleted forms nent finding in the multidomain pro- R R R R R R R R have been found in individuals with spinal muscular atrophy type I. teins involved in neuronal function and structure.1,2 Therefore, in addi- A A A P SHANK is a new family of scaffold proteins. Binding partners include N N N SH3 D SAM GKAP (a postsynaptic-density protein) as well as several neuronal tion to an increase in the protein rep- K K K Z G-protein–coupled receptors. ertoire, a substantial increase in the Figure 2. Schematic representation of the architecture of neuronal specific proteins that are expanded in number of protein interactions me- humans. Protein domains are represented by convention as different geometric shapes. Domain names diated by those domains is pre- are as follows: PDZ, domains found in diverse signaling proteins that may target signaling molecules to dicted in the human, as compared submembranous sites; SH3 (Src homology 3), domains often found in proteins involved in signal transduction related to cytoskeletal organization; GuKc, guanylate kinase homologues; IL, interleukin; with the fruit fly and nematode. Se- BIR, baculoviral inhibition of apoptosis protein repeat; NACHT, family of adenosine triphosphatase; LRR, lected examples of such novel verte- leucine-rich repeats; ANK, ankyrin repeats; and SAM, sterile ␣ motif. Biological descriptions of protein brate multidomain protein architec- domains and families are available through the Pfam10 (available at: http://www.sanger.ac.uk/Software/ 11 tures are provided in Figure 2. Pfam/index.shtml) and SMART (available at: http://smart.embl-heidelberg.de/) databases. NMDA indicates N-methyl-D-aspartate. A very important evolutionary difference between vertebrate and in- vertebrate nervous systems is the ap- Other protein families in- nels (Figure 1). Voltage-gated so- pearance of myelinating glial cells, volved in neural development, func- dium and potassium channels play which provide axonal insulation and tion, and structure, and absent in the a key role in the generation of neu- increase the speed of propagation of fruit fly and nematode, mediate cell ronal action potentials. Mutations in action potentials. The human ge- adhesion such as the connexin gap the voltage-gated potassium chan- nome has at least 10 genes in- junction proteins. These are sub- nel genes are involved in episodic volved in myelin production; only units of the intercellular channels ataxia/myokymia syndrome, auto- 1 gene related to myelin proteolip- that form electrical synapses in ver- somal dominant deafness type 2, and ids was detected in the fruit fly and tebrates. Mutations in the human benign neonatal epilepsy types 1 and none was detected in the nema- connexin genes are involved in dis- 2. Voltage-gated calcium channels tode. Mutations in genes involved in eases like X-linked Charcot-Marie- also play a central role in neuro- myelin production can result in se- Tooth neuropathy and autosomal transmitter release; mutations in vere demyelinating disorders such as dominant deafness type 3. Several some members of this gene family Charcot-Marie-Tooth neuropathy ion channel families show marked are responsible for disorders like epi- types 1A and 1B and Dejerine- expansions in the human genome, sodic ataxia type 2, familial hemiple- Sottas syndrome (Figure 3). for example, the voltage-gated chan- gic migraine, X-linked congenital

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 High Sequence Conservation Intermediate Sequence Conservation Low Sequence Conservation No Sequence Conservation Disease Name Gene Symbol OMIM No. Cytogenetic Location Fruit Fly Nematode Aceruloplasminemia CP 117700 3q21-q24 Achromatopsia CNGA3 216900 2p11.2-q12 Adenylosuccinase deficiency ADSL 103050 22q13.1 Adrenoleukodystrophy ABCD1 300100 Xq28 Albinism, ocular, type 1 OA1 300500 Xp22.3 α-Thalassemia/mental retardation syndrome, type 2 ATRX 300032 Xq13 Alzheimer disease, familial, early-onset PSEN1 104311 14q24.3 Alzheimer disease, familial, early-onset PSEN2 600759 1q31-q42 Alzheimer disease, familial, early-onset, APP-related APP 104760 21q21.3-q22.05 Amyloid polyneuropathy, familial TTR 176300 18q11.2-q12.1 Amyloidosis, cerebroarterial, Dutch type APP 104760 21q21.3-q22.05 Amyloidosis, Finnish type GSN 137350 9q34 Amyotrophic lateral sclerosis, due to SOD1 deficiency SOD1 147450 21q22.1 Angelman syndrome UBE3A 601623 15q11-q13 Apnea, postanesthetic BCHE 177400 3q26.1-q26.2 Ataxia with isolated vitamin E deficiency TTPA 600415 8q13.1-q13.3 Ataxia-telangiectasia ATM 208900 11q22.3 Autism, succinylpurinemic ADSL 103050 22q13.1 Biotinidase deficiency BTD 253260 3p25 Brunner syndrome MAOA 309850 Xp11.23 Canavan disease ASPA 271900 17pter-p13 Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy NOTCH3 600276 19p13.2-p13.1 Cerebrotendinous xanthomatosis CYP27A1 213700 2q33-qter Ceroid lipofuscinosis, neuronal type 1, infantile PPT 600722 1p32 Ceroid lipofuscinosis, neuronal type 2, classic late infantile CLN2 204500 11p15.5 Ceroid lipofuscinosis, neuronal type 3, juvenile CLN3 204200 16p12.1 Ceroid lipofuscinosis, neuronal type 5, variant late infantile CLN5 256731 13q21.1-q32 Charcot-Marie-Tooth neuropathy, X-linked 1, dominant GJB1 304040 Xq13.1 Charcot-Marie-Tooth neuropathy type 1A PMP22 601097 17p11.2 Charcot-Marie-Tooth neuropathy type 1B MPZ 159440 1q22 Charcot-Marie-Tooth neuropathy type 2A KIF1B 605995 1p36 Charcot-Marie-Tooth neuropathy type 4B MTMR2 603557 11q22 Choroideremia CHM 303100 Xq21.2 Cockayne syndrome type 2, late-onset ERCC6 133540 10q11 Coffin-Lowry syndrome RPS6KA3 300075 Xp22.2-p22.1 Color blindness, deutan OPN1MW 303800 Xq28 Color blindness, protan OPN1LW 303900 Xq28 Color blindness, tritan OPN1SW 190900 7q31.3-q32 Cone dystrophy, progressive CORD6 601777 17p13-p12 Cone dystrophy type 3 GUCA1A 600364 6p21.1 Cone-rod dystrophy type 3 ABCA4 601691 1p21-p13 Cone-rod retinal dystrophy type 2 CRX 602225 19q13.3 Cowden disease PTEN 601728 10q23.3 Creutzfeldt-Jakob disease PRNP 176640 20pter-p12 Deafness, autosomal dominant type 11, neurosensory MYO7A 276903 11q13.5 Deafness, autosomal dominant type 15 POU4F3 602460 5q31 Deafness, autosomal dominant type 2 KCNQ4 600101 1p34 Deafness, autosomal dominant type 3 GJB2 121011 13q11-q12 Deafness, autosomal dominant type 5 DFNA5 600994 7p15 Deafness, autosomal dominant type 8 TECTA 602574 11q22-q24 Deafness, autosomal dominant type 9 COCH 601369 14q12-q13 Deafness, autosomal dominant nonsyndromic sensorineural, type 1 DIAPH1 602121 5q31 Deafness, autosomal recessive type 3 MYO15A 602666 17p11.2 Deafness, autosomal recessive type 1 GJB2 121011 13q11-q12 Deafness, autosomal recessive type 2, neurosensory MYO7A 276903 11q13.5 Deafness, autosomal recessive type 4 SLC26A4 274600 7q31 Deafness, autosomal recessive type 9 OTOF 601071 2p23-p22 Deafness, X-linked type 1, progressive TIMM8A 304700 Xq22 Deafness, X-linked type 3, conductive, with stapes fixation POU3F4 300039 Xq21.1 Dejerine-Sottas disease, myelin P(0)-related MPZ 159440 1q22 Dejerine-Sottas disease, PMP22-related PMP22 601097 17p11.2 Dementia, frontotemporal, with parkinsonism MAPT 157140 17q21.1 Dentatorubropallidoluysian atrophy DRPLA 125370 12p13.31 Doyne honeycomb retinal dystrophy EFEMP1 126600 2p16 Duchenne muscular dystrophy DMD 310200 Xp21.2 Dystonia, progressive, with diurnal variation GCH1 600225 14q22.1-q22.2 Emery-Dreifuss muscular dystrophy EMD 310300 Xq28 Epilepsy, benign neonatal, type 2 KCNQ3 602232 8q24 Epilepsy, benign neonatal, type 1 KCNQ2 602235 20q13.3 Epilepsy, nocturnal frontal lobe, type 1 CHRNA4 118504 20q13.2-q13.3 Epilepsy, progressive myoclonic type 1 CSTB 601145 21q22.3 Epilepsy, progressive, with mental retardation CLN8 600143 8pter-p22 Episodic ataxia, type 2 CACNA1A 601011 19p13 Episodic ataxia/myokymia syndrome KCNA1 176260 12p13 Fragile X syndrome FMR1 309550 Xq27.3 Friedreich ataxia FRDA 229300 9q13-q21.1 Fukuyama congenital muscular dystrophy FCMD 253800 9q31-q33 Gerstmann-Straussler disease PRNP 176640 20pter-p12 GM2-gangliosidosis, AB variant GM2A 272750 5q31.3-q33.1 GM2-gangliosidosis, juvenile, adult HEXA 272800 15q23-q24 Gyrate atrophy OAT 258870 10q26 Hemiplegic migraine, familial CACNA1A 601011 19p13 Holoprosencephaly type 2 SIX3 157170 2p21 Holoprosencephaly type 3 SHH 600725 7q36 Huntington disease HD 143100 4p16.3 Hydrocephalus, X-linked L1CAM 308840 Xq28 Hyperekplexia and spastic paraparesis GLRA1 138491 5q32 Hypomyelination, congenital MPZ 159440 1q22

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Disease Name Gene Symbol OMIM No. Cytogenetic Location Fruit Fly Nematode Insensitivity to pain, congenital, with anhidrosis NTRK1 191315 1q21-q22 Insomnia, fatal familial PRNP 176640 20pter-p12 Juberg-Marsidi syndrome ATRX 300032 Xq13 Kallmann syndrome KAL1 308700 Xp22.3 Kanzaki disease NAGA 104170 22q11 Krabbe disease GALC 245200 14q24.3-q32.1 Leber congenital amaurosis, type I GUCY2D 600179 17p13 Leber congenital amaurosis, type II RPE65 180069 1p31 Leber congenital amaurosis, type III CRX 602225 19q13.3 Lesch-Nyhan syndrome HPRT1 308000 Xq26-q27.2 Lhermitte-Duclos syndrome PTEN 601728 10q23.3 Lissencephaly, X-linked DCX 300121 Xq22.3-q23 Lissencephaly type 1 PAFAH1B1 601545 17p13.3 Lowe syndrome OCRL 309000 Xq26.1 Machado-Joseph disease MJD 109150 14q24.3-q31 MASA syndrome L1CAM 308840 Xq28 Mental retardation, X-linked nonspecific RABGD1A 300104 Xq28 Mental retardation, X-linked, 60 OPHN1 300127 Xq12 Mental retardation, X-linked, FRAXE type FMR2 309548 Xq28 Metachromatic leukodystrophy ARSA 250100 22q13.31-qter NAGA deficiency, mild NAGA 104170 22q11 Neuropathy, congenital hypomyelinating, type 1 EGR2 129010 10q21.1-q22.1 Neuropathy, recurrent, with pressure palsies PMP22 601097 17p11.2 Niemann-Pick disease, type A SMPD1 257200 11p15.4-p15.1 Niemann-Pick disease, type C NPC1 257220 18q11-q12 Night blindness, congenital stationary GNAT1 139330 3p21 Night blindness, congenital stationary, X-linked, type 2 CACNA1F 300110 Xp11.23 Nodular heterotopia, bilateral periventricular FLNA 300049 Xq28 Norrie disease NDP 310600 Xp11.4 Oguchi disease, type 1 SAG 181031 2q37.1 Oguchi disease, type 2 RHOK 180381 13q34 Parkinson disease UCHL1 191342 4p14 Parkinson disease, juvenile, autosomal recessive PARK2 602544 6q25.2-q27 Parkinson disease, type 1 SNCA 163890 4q21.3-q22 Phenylketonuria PAH 261600 12q24.1 Phenylketonuria due to dihydropteridine reductase deficiency QDPR 261630 4p15.31 Phenylketonuria due to PTS deficiency PTS 261640 11q22.3-q23.3 Phosphoribosyl pyrophosphate synthetase–related gout PRPS1 311850 Xq22-q24 Pseudo–Zellweger syndrome ACAA 261510 3p23-p22 Refsum disease PHYH 602026 10pter-p11.2 Refsum disease, infantile PEX1 602136 7q21-q22 Retinitis pigmentosa, autosomal recessive CNCG1 123825 4p12-cen Retinitis pigmentosa, autosomal recessive PDE6B 180071 5q31.2-q34 Retinitis pigmentosa, autosomal recessive PDE6A 180072 4p16.3 Retinitis pigmentosa, autosomal recessive, RLBP1-related RLBP1 180090 15q26 Retinitis pigmentosa, digenic ROM1 180721 11q13 Retinitis pigmentosa, peripherin-related RDS 179605 6p21.1-cen Retinitis pigmentosa, rhodopsin-related RHO 180380 3q21-q24 Retinitis pigmentosa type 14 TULP1 602280 6p21.3 Retinitis pigmentosa type 2, X-linked RP2 312600 Xp11.3 Retinitis pigmentosa type 3, X-linked RPGR 312610 Xp21.1 Retinoschisis RS1 312700 Xp22.2-p22.1 Sandhoff disease HEXB 268800 5q13 Schindler disease NAGA 104170 22q11 Segawa syndrome, recessive TH 191290 11p15.5 Sialidosis NEU1 256550 6p21.3 Sjögren-Larsson syndrome ALDH3A2 270200 17p11.2 Spastic paraplegia L1CAM 308840 Xq28 Spastic paraplegia type 2 PLP1 312080 Xq22 Spastic paraplegia type 4 SPG4 182601 2p24-p21 Spinal muscular atrophy, HEXB-related HEXB 268800 5q13 Spinal muscular atrophy type 1 SMN1 600354 5q12.2-q13.3 Spinocerebellar ataxia type 1 SCA1 601556 6p23 Spinocerebellar ataxia type 10 SCA10 603516 22q13 Spinocerebellar ataxia type 12 PPP2R2B 604325 5q31-q33 Spinocerebellar ataxia type 2 SCA2 601517 12q24 Spinocerebellar ataxia type 6 CACNA1A 601011 19p13 Spinocerebellar ataxia type 7 SCA7 164500 3p21.1-p12 Stargardt disease type 1 ABCA4 601691 1p21-p13 Startle disease/hyperekplexia, autosomal dominant GLRA1 138491 5q32 Tay-Sachs disease HEXA 272800 15q23-q24 Thymine-uraciluria DPYD 274270 1p22 Tyrosinemia, type II TAT 276600 16q22.1-q22.3 Tyrosinemia, type III HPD 276710 12q24-qter Usher syndrome, type 1B MYO7A 276903 11q13.5 Usher syndrome, type 2 USH2A 276901 1q41 Waardenburg syndrome, type I PAX3 193500 2q35 Wilson disease ATP7B 277900 13q14.3-q21.1 Wolfram syndrome WFS1 222300 4p16.1 Zellweger syndrome PXMP3 170993 8q21.1

Figure 3. Comparative analysis of human genes implicated in neurologic diseases. A set of 168 human neurologic diseases resulting from specific alleles of 146 different human genes was selected from Online Mendelian Inheritance in Man (OMIM) for the comparative analysis. The proteins encoded by those genes were used as queries to search the nonredundant GenBank database for related proteins from Drosophila melanogaster (fruit fly) and Caenorhabditis elegans (nematode). BlastP searches were conducted as described,12 and the results were color coded according to their level of statistical significance, reflecting the degree of confidence in their evolutionary and functional relationship. BlastP E-values less than 10 −100, representing the highest degree of sequence conservation, are shown as dark-green bars. E-values between 10 −100 and 10 −40 are represented in blue-green color, indicating an intermediate level of conservation. E-values in the range of 10 −40 10 −6 are shown in light blue, indicating the lowest level of conservation. E-values greater than 10 −6 are shown as white bars, indicating absence of gene conservation. The OMIM disease entry numbers (available at: http://www.ncbi.nlm.nih.gov/Omim/) and cytogenetic locations are listed. APP indicates amyloid precursor protein; SOD1, superoxide

dismutase 1; PMP22, peripheral myelin protein 22; GM2, a ganglioside with the addition of N-acetylgalactosamine; FRAXE, fragile site in chromosome Xq28; NAGA, ␣-N-acetylgalactosaminidase; PTS, 6-pyruvoyltetrahydropterin synthase; RLBP1, retinaldehyde-binding protein 1; and HEXB, hexosaminidase B.

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 night blindness type 2, and spino- riopathy with subcortical infarcts and disease C1 gene, phenylalanine hy- cerebellar ataxia type 6 (Figure 3). leukoencephalopathy [CADASIL]); droxylase (phenylketonuria), cyclic The tubulin-binding proteins of the presenilin 1, presenilin 2, and amy- nucleotide–gated channel ␣-1 (reti- MAP2/tau family are involved in loid ␤-precursor protein (familial nitis pigmentosa), tyrosine hydroxy- dendrite and axonal morphologic early-onset Alzheimer disease); and lase (Segawa syndrome), and alde- determination, contributing to the superoxide dismutase 1 (amyotro- hyde dehydrogenase 3A2 (Sjo¨gren- development of neuronal morpho- phic lateral sclerosis). Genetic stud- Larsson syndrome). logic characteristics. Mutations in ies in the fruit fly have made impor- About 44% of the human genes the human TAU gene lead to fron- tant contributions to our under- in our selected set appear to have no totemporal dementia with parkin- standing of their cellular function counterparts in the fruit fly and sonism. and the molecular mechanisms in- nematode, including the genes in- We performed a comparative volved in neurodegeneration (re- volved in myelin production, gap analysis of 168 neurogenetic dis- viewed by Fortini and Bonini13). De- junctions, and voltage-gated ion eases selected from Online Mende- letion of the fruit fly ␤-amyloid channels discussed above. Other ex- lian Inheritance in Man. These dis- precursor protein–like gene leads to amples of those nonconserved genes eases result from specific alleles of behavioral defects that can be par- are neuronal ceroid-lipofuscinosis 2, 146 different human genes (Figure tially rescued by transgenic expres- 5, and 8; dentatorubropallidol- 3). The sequence homology analy- sion of the human amyloid precur- uysian atrophy; fragile X mental re- sis was done by means of BlastP as sor protein gene.14 Loss-of-function tardation 2; monoamine oxidase A described previously,12 and no sub- mutations in the fruit fly presenilin (Brunner syndrome); Norrie dis- jective judgments were done for gene cause neurogenic and other de- ease gene; prion protein gene orthologous genes, since these are velopmental defects.15 In the nema- (Creutzfeldt-Jakob disease, Gerst- often quite difficult to determine tode, deletion of the presenilin ho- mann-Strausler-Scheinker syn- for Caenorhabditis elegans genes.12 mologue sel-12 causes an egg- drome, and fatal familial insomnia); For the 146 human genes surveyed, laying defective phenotype that can spinocerebellar ataxia 7 and 10; and we found similar levels of sequence be fully rescued by normal human ␣-synuclein (familial Parkinson conservation in the fruit fly and presenilin but, interestingly, not by disease). Although the gene encod- nematode. About 56% of those human presenilins carrying muta- ing ␣-synuclein is absent in the fruit genes show high or intermediate tions linked to familial early-onset fly, expression of human ␣-synuclein sequence conservation in Dro- Alzheimer disease.16 The fruit fly has in Drosophila has been shown to pro- sophila (83 genes) and C elegans been a very useful animal model for duce loss of dopaminergic neurons, (81 genes). This is surprising given the study of the pathogenesis of poly- filamentous intraneuronal inclu- the fact that the nervous system in glutamine repeat diseases such as sions, and locomotor dysfunction the fruit fly is significantly more Huntington and Machado-Joseph dis- reminiscent of Parkinson disease.20 complex than that in the nematode. eases. Expression of polyglutamine- This suggests that fruit flies have There are 3 cases of gene conserva- expanded huntingtin and Machado- some conservation in the mecha- tion with the nematode but not the Joseph disease protein in the fruit fly nisms leading to neurodegeneration fruit fly: hypoxanthine phosphori- induced neuronal degeneration.17,18 in Parkinson disease, even though bosyltransferase 1 (involved in Lesch- An important advantage of the fruit one of its components (␣-synuclein) Nyhan syndrome), the Machado- fly and nematode animal model sys- may be absent. Joseph disease gene, and phytanoyl– tems is the application of large-scale coenzyme A hydroxylase (Refsum genetic screening methods to iden- INTERCHROMOSOMAL BLOCK disease). Four genes are conserved in tify novel genes that can modulate the DUPLICATIONS the fruit fly but not in the nema- molecular mechanisms of disease. A tode: otoferlin (autosomal recessive recent genetic screen identified 2 Dro- More than 1000 interchromosomal deafness type 9), fragile X mental re- sophila genes that appear to modu- segmental duplications have been de- tardation 1, spinocerebellar ataxia 2, late the polyglutamine-induced neu- tected in the human genome.1 Many and the sonic hedgehog homologue rodegeneration, which may lead to of these large block duplications ap- (holoprosencephaly type 3), a gene better understanding of pathogen- pear to have an ancient origin and are that was originally characterized in esis and ultimately to novel thera- likely to predate most vertebrate di- the fruit fly. peutic development.19 vergences, having undergone many Several human genes in our sur- Other examples of human genes subsequent deletions and rearrange- vey had counterparts in the Dro- involved in neurologic diseases that ments.1 The block duplications range sophila and C elegans genomes. Many have homologues in the fruit fly and in size from a few genes to segments of these have been well character- nematode are cyclic nucleotide– covering most of a chromosome. In- ized by molecular studies, particu- gated channel ␣-3 (achromatopsia), terestingly, many genes that have dis- larly with the fruit fly used as the ani- ␣-thalassemia/mental retardation syn- ease-associated alleles are present in mal model. Examples of such genes drome gene, adenosine triphosphate– the duplicated segments. Further- are diaphanous homologue (autoso- binding cassette D1 (adrenoleuko- more, in some instances the genes in mal dominant nonsyndromic deaf- dystrophy), platelet-activating fac- both duplicated segments have al- ness type 1); notch homologue 3 tor acetylhydrolase 1b ␣-subunit (lis- leles associated with similar dis- (cerebral autosomal dominant arte- sencephaly type 1), Niemann-Pick eases. We present examples of inter-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Paralogous Genes on Duplicated Genome Segments That Have Alleles Involved in Neurologic Diseases*

Gene Product Chr Disease OMIM Duplicated Gene Product Chr Disease OMIM Sine oculis homeobox 2 Holoprosencephaly 2 603714 Sine oculis homeobox 14 ...... (Drosophila) homologue 3 (Drosophila) homologue 1 Sine oculis homeobox 2 Holoprosencephaly 2 603714 Sine oculis homeobox 14 ...... (Drosophila) homologue 3 (Drosophila) homologue 6 G protein ␣-transducing 3 Night blindness, congenital 139330 G protein ␣-inhibiting activity 7 ...... activity polypeptide stationary subunit 1 Synuclein, ␣ 4 Parkinson disease, type 1 163890 Synuclein, ␥ 10 ...... Hexosaminidase B 5 Sandhoff disease 268800 Hexosaminidase A 15 Tay-Sachs disease 272800 (␤ polypeptide) Tyrosine hydroxylase 11 Segawa syndrome, recessive 191290 Phenylalanine hydroxylase 12 Phenylketonuria 261600 Phenylalanine hydroxylase 12 Phenylketonuria 261600 Tyrosine hydroxylase 11 Segawa syndrome, 191290 recessive Potassium voltage-gated 12 Episodic ataxia/myokymia 176260 Potassium voltage-gated 1 ...... channel 1 syndrome channel 3 Potassium voltage-gated 12 Episodic ataxia/myokymia 176260 Potassium voltage-gated 1 ...... channel 1 syndrome channel 10 Connexin 26 13 Deafness, autosomal 121011 Connexin 32 X Charcot-Marie-Tooth 304040 dominant 3 neuropathy, X-linked 1, dominant Cochlin precursor 14 Deafness, autosomal 603196 AC007363—similar to 2 ...... dominant 9 Coch-5B2 Hexosaminidase A 15 Tay-Sachs disease 272800 Hexosaminidase B 5 Sandhoff disease 268800 (␤ polypeptide) Microtubule-associated 17 Dementia, frontotemporal, 157140 Microtubule-associated 2 ...... protein tau with parkinsonism protein 2 Lissencephaly 1 protein 17 Lissencephaly 1 601545 G protein ␤ polypeptide 5 ...... 2–like 1 Connexin 32 X Charcot-Marie-Tooth 304040 Connexin 26 13 Deafness, autosomal 121011 neuropathy, X-linked 1, dominant 3 dominant Connexin 32 X Charcot-Marie-Tooth 304040 Connexin 30 13 ...... neuropathy, X-linked 1, dominant Connexin 32 X Charcot-Marie-Tooth 304040 Connexin 46 13 ...... neuropathy, X-linked 1, dominant

*Chr indicates chromosome number; OMIM, Online Mendelian Inheritance in Man disease entry number; and ellipses, not applicable. †Available at http://www.ncbi.nlm.nih.gov/Omim/.

chromosomal duplicated segments night blindness. A duplicated seg- tyrosine hydroxylase, which are, re- associated with neurologic diseases ment containing the G protein ␣-in- spectively, part of a segment dupli- (Table). The homeobox genes sine hibiting subunit 1 gene is present in cated in chromosomes 12 and 11. oculis homologues 3, 1, and 6 are lo- chromosome 7 (Table). Phenylalanine hydroxylase muta- cated in duplicated segments in hu- The ␣-synuclein gene, associ- tions are associated with phenylke- man chromosomes 2 and 14. The ated with familial Parkinson disease, tonuria, and tyrosine hydroxylase mu- Drosophila sine oculis gene is a tran- is located in a chromosome 4 seg- tations are linked to autosomal scription factor that plays a crucial ment that is duplicated in chromo- recessive Segawa syndrome, a dis- role in morphogenesis, and its mu- some 10, where the ␥-synuclein gene ease with levodopa-responsive par- tant alleles lead to defects in eye is located. The chromosome 15 gene kinsonism that appears early in in- morphologic features and neuronal hexosaminidase A is associated with fancy (Table). The gene coding for development. Mutations in the hu- Tay-Sachs disease, an autosomal re- voltage-gated potassium ion chan- man sine oculis homeobox homo- cessive progressive neurodegenera- nel 1, linked to episodic ataxia syn- logue 3 gene are associated with neu- tive disorder that is prevalent in the drome, is located in a chromosome 12 rodevelopmental alterations in Ashkenazi Jewish population. A du- segment that has duplications in chro- holoprosencephaly type 2. The G plicated segment in chromosome 5 mosome 1 containing 2 paralog genes protein ␣-transducing activity poly- contains the hexosaminidase B ␤ of the Shaker-related subfamily of peptide 1 gene in human chromo- gene, which is associated with Sand- voltage-gated potassium ion chan- some 3 encodes a transducin ␣-sub- hoff disease, a disorder clinically simi- nels (Table). The cochlin precursor unit involved in the stimulation of lar to Tay-Sachs disease, but ob- gene in chromosome 14 linked to au- cyclic guanosine monophosphate– served mostly in non-Jewish patients. tosomal dominant deafness type 9 phosphodiesterase in rod photore- Another example of 2 paralog genes is duplicated in chromosome 2. ceptors, and its mutations are asso- associated with neurogenetic dis- The gene coding for microtubule- ciated with congenital stationary ease is phenylalanine hydroxylase and associated protein tau in chromo-

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