From Gene to Phene*

FROM GENE TO PHENE*

JAN H. PORTER, M.D.

INTRODUCTION acid. The normal (:J-c hain is made up of 146 a m ino acids a nd as each a mino acid is coded for b y a trio Chromosomes are t he o rgans o f heredity. T hey of DNA bases, the gene determining t he c hain carry t he ge nes, the units of heredity . must contain 438 bases. Since the mutation caus Chromosomes transmit groups o f ge nes fr om one in vo lves the 6th trip let in ge neration to the next, and ge nes mediate the_ ing t he sickl e cell allele 7th, a nd 18th b ases inheri ted m essage by directing t he synt hesiS of the sequence - the 16th, 1 and since adenine has bee n changed for thymine polypept ides. We s hould, t herefore, be a bl ~ to relate a gi ven characteristic (phenotype) of an on one o f the t wo complementary strands of the DNA, it must be t he 17th base t hat is replaced by individual to a s peci fic ge ne (genotype) . Indeed, a e findings in sickle cell full account of a g iven characteristic s hould start another. Alm ost all th disease can be ex plained by the phys ical proper with the type and sequence of t hose d eoxy rib o n~ ties of reduced hemoglobin S, particul arly by i t cl eic ( DNA) bases which m ake up t he ge ne m low solu bili ty at low oxygen tension . This may question, then correlate t his wi th the type a nd resul t fr om an alteration in a s mall region on the sequence of t hose amino acids in ~ h e e ~ zym~. or ule by t he substit ution protein it controls, proceed to e lu cidate Its eff ect surface of the p rotein molec on the a ppropriate bioc hemical pathway , and of the hydrophobic v aline for a hydrophilic glu relate this to the phenotype ( Fi g. 1). Finall y, we ta mic acid residue (Fig. 2) . should be able to assign a g iven ge ne to a s pecifi c There a re t hree categories in which changes in genetic materi al can lead to cl inical disorders: (1) chromosome. DNA has two c haracteristics: it is remarkably m ajor mutant ge nes, (2) polyge nic d isorders, and stable a nd it replicates identically. If t his we re not (3) c hromoso mal abnormali ties. so the o rderly development o f an individual and t h ~ stability of the species wo uld not be possible. MAJOR M UTANT GENES If on the other hand, we were a ll identical, the McKusick (1971) lists 1,896 clinical condit ions. have arisen q~estio n of in heritance might never varying g reatly in manifestation and severity. since the diffe rences provide t he o bservational caused b y a s ingle ge ne w ith an abnormal effect. refully we uni ts of genetics. Indeed, t he more ca Some a re present at birth or appear short!) individu examine o urselves the more our unique afterwards; others may not become apparent u ntil ali ty b ecomes appa rent. One of the causes of middle o r l ate li fe. Some a re inevitabl y progres individual variation is mutation which can b e sive a nd fatal; others cause only minor disability. vari ation. A defined as the inception of heri table Any o rgan or tissue can b e affected, and chara - a s ingle ge ne mutation co nsists of a c hange in teristic a nd specific pathological changes are often one code nucleotide, whi ch leads to a c hange in demonstrable d . Consequently, the a ltered ge ne w ill specify wor If one ge ne o f a homologo us pair becomes id e in whi ch one a mino acid is replaced a polypept mutated to cause a n abnormali ty, we refer to the of diffe ~ by a nother. Such changes are t he start co ndition as autosomal dominant ; if both gen es of ences between all eles. After a ge ne has changed, It a homologous pair must be mutated to cause an d in its new state by replication. Thus, is p reserve abnormali ty, we call it a utosomal recessive. medical ge neti cs is t he study o f those differences t hat result in disease. The diffe rences in the ge notype whi ch, under certain circumstances, Dominant conditions lead to disease are merely a selected sample of all In an autosomal dominant condition , t he pa the differences that make each one of us unique. tient is a heterozygo te (Fig. 3): only one ge ne of a It is not yet feasible to define t he abnorma li ty in homologous pair resul ts in the abnormal effect. any ge netic co ndition by direct examination of the Homozygotes are rarely seen because most of the sequence of the DNA b ases of the a ppropri ate genes that give rise to dominant conditions with ge ne. But we can d educe the abnorma li ty in the an abnormal effect are in frequent (F ig. 4). M ore DNA by isolating t he a bnormal protein and deter over, such patients are probably even m ore se mining t he st ructural defect. In sickl e cell di sease, ve rely affected than heterozygotes and so d ie in for example, the various clinical and pathologic fetal or {!a rl y li fe . Nine hundred and fo rty-three features are due to the synthesis o f a n abn ormal dominant condit ions a re listed b y McKusick hemoglobin which differs fr om n ormal in only a (1971) (Table I). sin gle a mino ac id , i.e., at the 6th p os ition in t ~ e Little is kn ow n about t he nature of the b a ic (:J- polypeptide chain, valine replaces glu tamic defects in dominant condi tions. One does not find s uch elegant ident ification of the molecul ar pa • From the B irth D efects In stitute, New Y ork State Department o f H ealth, _Albany, and the D epartment o f t hology as have .been found in , fo r example, s ickle Pedi atrics, Albany Medtcal Coll ege, Albany, New York. cell disease. On the other ha nd , biochemical 360 GENE TO PHENE 361

advances have brought us a clearer understanding errors of metabolism are recessive and the defect of recessive disorders. is usuall y a deficiency in the activity of a specific enzyme. In heterozygotes, the e nzyme activity is R ecessive Conditions intermediate, a degree of deficiency that is seldom In an autosomal recessive condition, t he patient severe enough to impair metabolic function. is a homozygote (Fig. 5): both genes of a homolo Sometimes t he toxic effect of abnormall y high gou s pair have the abnormal effect. Although concentrations of normal metabolites causes t he heterozygotes are relatively co mmon, t hey are injury, as in phenylketonuria (Fig. 8). us ually not seen because under ordinary circum stances t hey are quite norma l (Fig. 6). Seven X -linked Conditions hundred and eighty-three recessive co nditions are The rules of dominance and recessivity also listed by McKusick (1971) (Table I). apply to sex-linked (or better X-linked) inheri We examine a trait in many different ways, i.e. tance (Fig: 9) . But since t he homologous genes clinically, biochemically, immunologically, and so ex ist only in women who have two X chromo on. It is, therefore, necessary to specifY how we somes, onl y in t hem do X-linked genes have a look at t h e t rait before we use t he te rms " domi dominant or r ecessive effect lik e a utosomal genes. nant" and "recessive." For example, sick le ce ll T he problem of dominance or recessivity does not disease is a recessive co ndition but the s ickling arise in men, who have only one X c hromosome phenomenon (seen when red cell s are exposed to and therefore lack paired X-borne genes. If a man sodium b isul fite) is dominant (Fig. 7). All in born carries a gene with an abnormal effect in hi s X-chromosome, he is abnorm al; if he carries a ge ne wit h a normal effect in his X-chromosome, he is normal. Because boys do not receive their fathers' X-chromosome, the characteristic fi nding AMINO ACIDS + in X-linkage is t he absence of male-to-male trans s- RNA mission (Fig. 9). One ~ hundred and fifty X-linked m -RNA co nditions are listed by McKusick (1971) (Table I).

DISORDERS OF MULTIFACTORIAL ETIOLOGY j In many common diseases that are clearly not inherited in a simple mendeli an manner, there is obviously an underl yi ng ge netically determined predisposition, whi ch is reflected in a rel ative ly hi gher conco GROWING CHAI~S rd ance rate among monozygotic than CO MPLETED among dizygotic twins and a higher frequency ~- POLYPEPTIDE CHAIN among relatives of patients t ha n in the general PROTEIN population. So fa r, t hese co ngeni tal defects have MOL ECULE not been id entifi ed nor associated wit h single metaboli c defects FIG. 1. D iagrammatic representation or protein syn nor with detectable chromoso thesis. mal a.nomali es. Rather t hey are determined by

RNA COOON UAG .....UU G l /\M IND ACID GLUTAM IC AC ID-VALINE j {J - CIIAIN TERM INAL PEPTI DE /~ PRIMA RY GE NE EFFECT S CHAN GE IN I SOELECTR IC CIIAN GE IN PO INT ON SOLUB ILITY EL EC TROPH ORES IS / '-...... CLINICAL PI CT URE SICK LI NG / l '---.... ABDOMINAL PA IN IIEMOLYSIS RENAL EFFECTS ~ I FA iLURE ro------.... ANEM IA RET ICU L OCY TO SI S JAUND ICE CO N ~~~TERA T E II EMA TU RIA /~ COMPE NSA TORY HEMOPO I ES I S CARD IAC FAILUR E /'-...... llcPATO S PL ENOMEGA LY MARROW IIYPE R PLASIA ! RU PTURE OF SPLEEN

FIG. 2. The pedigree or causes ror sick le cell anemia. 362 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

AUTOSOMA L DOM INANT COND ITI ONS

e PATIENTS ARE HETEROZYGOTE$.

e 50 % OF CHILDREN ARE AFFECTED REGARDLESS OF SEX .

e PAT IENT S HAVE ONE AFFEC TED PARENT (UN LE SS THE GENE WITH THE ABNORMAL EFFECT wAS THE RESULT OF A NEW MUTATION).

(] u HETERO ZYGO US MAN AND WOMAN

FIG. 3. Characteristics of autoso mal dominant co nditions.

In general, t he recurrence risk for an affected INCIDENCE OF first-degree relative of a s ingle affected person is HOMOZYGOUS DOMINANT low (about 5 percent) and reflects t he interaction of multiple genetic and environmental factors. AFFECTED Moreover, in conditions determined by m ajor HETEROZYGOTE the risk of recurrence is constant I :5000 mutant genes regardless of whether t he parents have had one or more affected children, whereas in polygenic con MARRIAGE OF n HETEROZYGOTE$ ditions, the ri sk of recurrence varies since it is not 1'5000x 1'5000, a matter of the presence or absence of a gene with I: 25,000,000 an abnormal effect but of the family's average component of risk. In fact, t he more members of ill HOMOZYGOTE 8 the family affected anc;l the more severe the 1:25,000,000x "" ' 1· 10 m a!formation in the proband, the higher the risk of recurrence. In addit ion, if t he patients wi t h the FIG. 4. Hypothetical incidence for a homozygote of a condition are preponderantly of one sex, the ri k dominant condition with a heterozygote incidence of will be higher to relatives of the less frequen tly 1: 5000. affected sex·, who are predisposed to be more extreme devia nts. polygenic inheritance, that is, by t he in teraction The analysis of family data has led to the of all eles at a number of different loci , each following general conclusions: (1) The etiology of contributing a small effect. Environmental factors these disorders is multifactorial, involving many also play a s ignificant role in t he determination of different hereditary and environmental in fl~ polygenic di sorders of multifactori al etiology. The ences. (2) Their heredita ry component is poly evidence for polygenic inheritance is based upon genic, i.e., they reflect the activity of many gene data of incidence in the ge neral population and of and result in a continuum of the genetic predispo the fa milia! recurrence of particular malforma sition (Fig. 10). (3) Their actual expression re tions (Table IT). quires a strong genetic predisposition that pushe Thus, for example, in anencephaly and s pina the individual beyond the " threshold of risk, " at bifida, if two ch il dren in a fa mily are already which point environmental influences determine affected, the incidence in subsequent children is whether and to what extent the patient is affected. tw ice that in fa milies where on ly one ch ild was previously affected. S uch empiri cal data are also CHROMOSOMAL ABNORMALITIES avai lable for cleft lip and palate, atrial septal Chromosomal abnormali t ies associated wi th defect, conge nital pyloric stenosis, club foot, dia pathologic conditions are t he result of alteration betes mellitus, and psoriasis (Watson and Carr). in the number or the structure of chromosomes. GENE TO PHENE 363

TABLE l Examples of conditions w ith various modes of inheritan ce

Autosoma l Domina nt Autosomal Recessive X -linked

Acan t h os is ni gri cans Albin ism An giokerotoma corporis diffusion Angioneurotic edema Ataxia telangiectasia Anhidrotic ectodermal dysplasia Ehler- Dan los syndrome Bloo m's syndrome Color blindness Epidermolys is bullosa simplex Chedi ak- Higashi syndrome Hemophilia A and B H ereditary hemorrhagic telangiectasis Cockayne's syndrome Hunter syndrome Marfan syndrome Epidermolysis bullosa dystrophi ca Icht hyosis vu lgaris Milroy's disease Erythropoietic poryphyri a lncontin entia pigmenti Nail-patell a sy ndrome Homocystinuria K allmann syndrome Neurofibromatosis Hurler syndrome Wiscott- Aldrich syndrome Peu tz- Jeghers syndrome Lipoid protein osis Porph y ria va ri egata Phenylk etonuria Tuberou s sclerosis Pseudoxanlhoma elaslicum Waarde nburg's syndrome Werner's syndrome Xan t h o matosis Xeroderma pi gmenlosum

AUTOSOMAL RECESS IVE CONDITIONS

e PATIEN TS ARE HOMO ZYGO TES. e 25 % OF CHI LD REN ARE AFFECTED. e 50 % ARE CARRIERS REGARDLE SS OF SEX. e PA TIENT S HAVE APPARENTLY NORMAL PARENTS. e THE RARER TH E CONDITION, THE HIGHER THE PROPORTION OF CO NSANGUINITY . II

IJ () HETEROZYG OUS MAN AND WOMAN

1111 HOMO ZYGO US MAN

Ftc. 5. Cha racteri stics of autosoma l recessive conditions.

N umerical Altera tions chromoso mes stick together; t hus one daughter ce ll gets both partners a nd the other n either (Fig. For a n irregul ar number of chromosomes, we 11) . The res ul t is one ga mete with 22 chromo use the term a neuploid. If one of a pa ir is mi ssing, somes and one wi t h 24. If the gamate with 22 the number of chromosomes is 45 and we refer to chromo omes is fe rt ilized by a normal gamete, a the condition as rn onoso my. If t here are t hree zygote wit h 45 chromosomes (monosomy) is pro instead of t wo homologous chromosomes, t he duced. If, on t he o ther hand. a gamete with 24 number of chromoso mes is 47 a nd we refer to t he chromoso mes is fert ili zed b y a normal gamete, a conditio n as trisomy. Monosomy a nd t ri somy, t he zygote with 47 chromosomes (tri so my) is pro most common aneuploidies, are caused by meiotic duced. nondis junction. Autosomal and sex chromosomes t risomies are Meiotic nondisjunction. Wh en h omologous · co mmon; except for one sex chromosome mon chromosomes fa il to separate a t anaphase, nondis osomy, the Turner syndrome, which i s relative ly junction resul ts. Instead of partin g at cell d ivision co mmon, monosomies are rare. and each go ing into a daughter cell , t he two Mitotic nondisjunction. Nondisjunction before 364 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

ore fertili zation (i.e., during meiosis) leads to the co nstit utions will result and, hence, two or m production of patients co mposed entirely of one ce ll lines will develop (Fig. 12). nuclear abnorm al chromosome cell line. If, however, non Anaphase lag has t he same e ffe ct. The a disjunction occurs a fter fertilization (during mito membrane shutt ing down suddenly excludes her sis), ce ll s with two or mo re different chromoso me laggard chromosome. This c hromoso me is e it included in the wrong cell , wh ich t hus receives an extra chromosome, or excluded and lost. If these INCIDENCE OF errors occur at the first cell division after fert ili za- HETEROZYGOUS RECESSIVE

SINGLE BASE UNAFFECTED CHANGE HETEROZYGOTE 1' 20

MAR RIAGE OF II HETEROZYGOTES GENES 1:20xl ' 20; I AOO ENZYMES AFFECTED ][ HOMOZYGOTE 1:400x ~4 ; 1' 1600 I i J"""ACID SUBS '"'"·TITUTIO N o< ,8 0 FIG. 6. Hypothetical incidence for a heterozygote of a recessive condit ion with h omozygote incidence of METABOLIC 1: 1600. 3LOCK o< 6 0 $ ® A____. o DOMINA NT CO· DOMINANT s --.c , ... REC ESSIVt ~b@ N URINE x____..y -P z @)

• Hb·S FIG. 8. Diagrammatic representation showing a s in • Hb- S DISEASE (mutation) leading to a s ingle amino POSI TI VE 0 Hb-A gle base change (]} on causing a metabolic block which may 0 ) CLINICALLY ~ SICKLING TEST acid substituti Q j NORMAL :5lHb-SA have one o f the foll ow mg consequences: (1) High l evels of the substrate, (2) A deficiency of the substance distal of an a bnormal protein , (4) FIG. 7. Pedigrees demonstrating t he c ircumstances to the bl ock, (3) Production urine, a nd (5) under wh ich t he hemoglobin S gene can b e consid ered to Excess excretion of the substrate in the . have a recessive , dominant, or codominant effect. Secondary metaboli c blocks

X- LIN KE D CONDIT ION S

e AFFECTED BOYS ARE HEMIZYGOTE$.

e 50 % OF SONS ARE AFFECTED.

e 50% OF DAUGH TERS ARE CARRIER S.

e MA LE TO MAL E TRAN SMI SS IO N NEVER OCCUR S.

41[) HETERO ZYGOU S WOMAN 1111 HEMIZYGOUS MAN

FIG. 9. Characteristics of X-I inked conditions. GENE TO PHENE 365

TABLE II In creased risk of relatives having the same malformation a s a propositus (From Carter, 1965)

Cleft lip plus Congeni tal dislo- Pylori c Talipes Anencep haly- or minus cleft meningomyelo- palate ca tion of hip stenosis equmovarus cele

Inc ide n c e in ge neral population 1/1 ,000 1/ 1,000 2/1,000 1/ 1,000 2/1,000 Inc ide n ce in relatives vs. in- c idence in general pop- ul a tion 1st d egr ee relatives 35 x 40 x 20 x 20x 8 x 2nd d egree relatives 7x 4x 5 x 5x - 3rd d egree relatives 3x 1.5 x 2x 2x 2x

HYPOTHETICAL DISTRIBUTION OF MULTIFACTORIAL GENOTYPES IN MALES AND FEMALES

X-CUT OFF i LIN E I :oI 1 MALES : A T RISK I DISJUNCTION.,__ METAPHASE~ NON-DISJUNCTION I I I 1m FIG . 11. The production or monosomic and trisomatic I FEMALES AT RISK sister nuclei by meiotic nondisjunction.

FEMALE MALE MEAN MEAN ~ 2I F IG- 10. Hypothetical distri bution of' multifactori al genotyp es in boys and girls. ~ :?:,~:;~ ~"~"><'~~

NORM AL NON- NORMAL NOR MAL tion , two cell lines with diffe rent c hromoso me MITOSIS DISJUNCTION MI TOS IS MITOS IS constit u t io ns resul t . If nondisjunction occurs a fter the first c leavage division, t hree cell lines wi th @@@@ @@@@ differe n t chromosome co nstitutions result. THREE CELL LINE S TWO CELL LI NES Mosaic is m is t he presence in an organism of two or mor e cell lin es, different either in chromosome ber o r structure but arising from the same F 1G. 12 . The prod uction of chromosomal m osaicism num by mitotic nondisjunction. zygote. The distribution of ce ll types in a mosaic varies f r o m t issue to tissue. One tissue may S tructural Alteration (Fig. 13) co ntain o nly one type, whereas others may co ntain entire ly different types. In others, the t issues are Stru ctural changes are the resul t of chromo co m p osed of all t he types, but t he ratios vary fr om some breaks. If the c hromoso me has no cen one t issue to another. Thus, many co mbinations tromere, a piece may break off a nd be lost during of norma l a nd abnorm al cells can occur, varyin g in cell division, a case of simple deletion. Such propor t io n in vari ous tissues; the phenotype of the deletions have been f ound in several groups to be patien t is d etermined by t he number and distribu associated wi t h co nge ni tal a bnormali t ies . Some tion of t h e ce ll lines . times pi eces of both ends of the same chromosome In some cases of chromosom al mosaicism, o ne break off simultaneo usly a nd get lost. If the stem line proliferates at the e xpense of others. broken ends join wit h each other, a ring chromo This h as b een demonstrated by a compari son of some is formed . Ring c hromoso me formation of the ratios of the vari ous stem lines at different ages several of the a utosomes and the X andY chro mo in patie n ts with mosaicism. Thus, patients wh ose some is associated wi t h co nge ni tal abnorm ali ties. clinical s ig ns do not match their chromosomal Instead of b ein g lost during cell division, a find ings m ay be mosaics in wh om one stem line detached piece of chromoso me sometimes be has dis placed another after the latter h as deter com es attached to, or inserted in to, another chro mi ned t he course of subsequent development and mosome. This in vo lves two simultaneous breaks of hence t he phenotype of the patient. different c hromoso mes. Since no chromosome rn a- 366 THE JOURNAL OF INVESTIGATIVE DERMAT OLOGY

BREAKAGE REUNION METAPHASE AP PEARA NCE

I. DELETION ~ ~ LOST .. SHORTENED 0~~ ~~ c O•

2.RING CHROMOSO ME FOR MATION @" ~ ~ E F G tjH @)) H~ o--e 3. REC IPROCAL TR ANSLOCATION ~ -- , ~i ~~ ~ ~"" . CENTRIC FUSION T 4 H r ~~ U SHORT ARMS ~ 5. ISOCHROMOSOME FORMATION - ~ -- LONG @ARMS OG

F1 c. 13. Structural chromosomal anomali es . terial i s lost, t here is no phenotypic a lteration. mosome structure. If a gamete in whi ch a recipro When, however, t he c hromosome carrying t he cal translocation is present becomes fertilize d by a extra c hromosome is passed on to the next genera normal ga mete, zygotes wi t h n ormal as well as tion, t he extra piece will be p resent i n addit ion to balanced chromosomal constit utions m ay result. a normal diploid co mplement . This segment is A zygote with a balanced chromosomal constitu t hen present in triplicate, a part ial trisomy. Dur tion d evelops in to a phenotypically normal per in g t he exchange of chromosome material between so n. Such peopl e will, however, run a considerable t wo c hromosomes, there is probably no ga in wit h ri sk of havin g miscarriages and children with out some associated d eficiency; hence with pa r co nge nital abnormalities as a resul t o f producino t ial trisomy, t here may also be partial monosomy. zygotes wi t h unbalanced chromosome co n st i tu~ Thus, as a result o f d eletion, we may get: (1) tions. The important poin t is t hat translocation co mplete loss of a chromosome, leading to mono chromosomes can be inherited t hrough phenotypi somy, as in t he Turner syndrome, where one of t he cally norm al carriers. X chromosomes is missing; (2) part ial d eletion, An isochromosome is a perfectly metacen tric leading to partial monosomy, as in s imple dele chromosome wi t h t wo completely homologou tion, ring c hromosome fo rmation, a nd duplica arms uni ted at t he cent romere. It a rises by t rans tion, i.e., deficiency states resul tin g from recipro ve rse instead of longitudinal splittin g of t he cen cal translocation . t romere at t he beginning of anaphase. It carries in Clinically, t he part ially deleted fr agments are duplicate t he same gene loci of the single chromo especiall y important when they are involved in some a rm which it represents. Isochromosom e of t ranslocations. Interchanges between eit her ho t he long a rm is quite a co mmon structural abnor mologous o r n onhomologous c hromosomes are mali ty of t he X chromosome. but called r eciprocal t ranslocations. Breaks are as The effe cts of chromosomal imbalance vary, sumed to take p lace at or n ear t he cent romere o f there is one im portant poin t: t he exclusion of a two nonhomologous c hromosomes and to be fol chromosome has more serious consequences than lowed b y t ranslocation and rejoining. T he process t he a ddit ion of a chromosome to t he normal is called centri c f usion because t he c hromosomes d iploid com plement . Autosomal monosomy is al rejoin in regions close to the centromere. I t con most always lethal, but t here a re t hree groups of verts two acrocentric chromosomes in to one meta chromosomes-D, E, and G -from which viable cent ri c c hromosome plus a s mall fr ag ment that trisomy syndromes ari se. Sex chromosom al mono in vari ably d isappears in subsequent cell di visions. somy, the 45, XO Turner syndrome, is viable. the The result of reciprocal translocation is t he loss of alt hough i t is a more seri ous condit ion t ha n the chromosome materi al and t he alteration of chro- sex chromosome t ri somy syndromes such as GENE TO PHENE 367

XXY Klinefelter and XXX syndro mes. T he 45, CONCLUSION: HETEROGENEITY XO chromosome constitut ion is surpri singly com mon, probably as much as 5 percent, in spontane When a genetic condit ion is examined closely, ous abortion: About 98 percent of XO embryos are heterogeneity is usually discovered . That which aborted. first appeared to be a si ngle cl inical phenotypic We think of chromosome anomali es as being entity is often found to be several clinically similar associated with congen ital abnormalities, but but ge neticall y a nd biochemically distinct orders. chromosome variation is detectable in apparently Genetic heterogeneity is of special interest and normal people: (1) About 0.5 percent have struc importance in the diagnosis of hereditary diseases. tural rearrangements such as pericentric inver Similar phenotypes can be produced by: sions and reciprocal translocations. (2) About 3 1. Mutations of different nucleotides within the percent have structural anomalies of an autosome, same ge ne, exemplified by the hemoglobinopa particularly in groups D, E, a nd G. These a noma thies. T hus, each chain is co ntroll ed by a different lies occur in the vicinity of secondary constri ctions ge ne yet we find many different abnormal h emo and can be inherited. (3) About 3 percent of men globins produced by mutations of the gene con have variation of the Y chromosome, and occa troll ing the ~-c h a in (Fig. 14) . sionally t heY may have some structural anomaly. 2. Mutation of different ge nes (genocopies) (4) The proportion of ce ll s with 45 chromosomes which can be detected by (Table I): increases with age. In women, this is due to the a. Clinical observations. For example, in the loss of a n X chromosome; in men, to the loss of a Y. epidermolysis bullosa syndromes, among whi ch

,8 - chain po s ition

Hb-va ri ants l 2 3 6 7 26 63 67 12 1 146 Val • • Hi s • • Leu • • G,l u • • Giu •• Glu •• His . • • Val • • ••••• Glu • • •• His Hb-S Val t Hb- C Lys j Hb-Gsan Jose Gl y Hb-E LIys Hb- Msaskatoon Tyr + H b-Zurich Arg

Hb- MM i I waukee Gl u

Hb-D Punjab Glu .NH t 2 Hb-OArabia Lys

F' IG. 14. Map of some !3-chain hemoglobin variants.

TABLE III Hereditary mucopolysaccharidoses Name Physical Mental Transmission Anoma lies Defi ciency Urin ary MPS

Hurler Autosomal recessive ++ ++ Derma tan sulfate, keratan sulfate Hunter X-Iinked ++ +1- Dermatan sulfate, heparin sulfate Sanfilippo A Autosomal recessive + +++ Heparin sulfate, (dermatan sulfate) Sanfilippo B Autosomal recessive + ++ + Heparin sulfate, (dermatan sulfate) Morquio Autosomal recessive +++ - Keratan sulfate Scheie Autosomal recessive + - Derma tan sul fate, heparin sulfate Maroteaux- Lamy Autosomal recessive ++ - Dermatan sulfate "Atypical " Autosomal recessive ++ - ? 368 THE JOURNAL OF INV ESTIGATIVE DERMATOLOGY some are relatively benign and others lethal, some It is t hrough t he demonstration of s uch h etero are dominant and others are recessive condit ions. geneity t hat t he pathogenic mechanis ms involved b. Genetic observations. For example, wit h the in genetic disorders will be recognized a nd it is Marfan syndrome and homocystinuria, the fo rmer only t hrough an exact knowl edge of each step from is a dominant and t he latter i s a recessive condi the gene to the phene t hat we can h ope to t ion. a meli orate, treat, or prevent disease. P e rhaps c. Linkage relationships. An example is t he more important in the biologic sense, t he discov deutan color blindness ge ne whic h is quite close to ery of vari ants tell s us something about a person'. t he hemophili a A ge ne but a long way from t he protein repertoire w hich represen ts t he m etabolic hemophilia B (Christmas disease) gene in t he milieu wit h which e nvironmental factors interact X-chromosome. to produce an individual's uniq ueness which , on d . Biochemical methods. Among t he mucopoly rare occasions, is expressed as disease. saccharidoses, t he Hunter factor (a protein) will I am grateful to Mrs. Ellen J. Heenehan for h er help in correct the defect in cul tured fibroblasts from a the preparation of this manuscript and to M cGraw-Hill patient with t he Hunter syndrome without affec t Book Company for allowing me to use illustrations from ing norm al cell s or cell s derived from patients with Heredity and Disease (Porter, 1968). other types of mucopolysaccharidoses by ac ce lerating mucopolysaccharide degradation REFERENCES (Table III). 3. Chomosomal anomalies. Ma le hypogonad Carter, C. 0. (1965). The inheritance of common con ism may be associated wi th Klinefelter syn genital malformations. Progr. Med. Genet., 4:59-63. drome (47,XXY), the Kallma nn syndrome, McKusick, V. A. (1971). M endelian Inheritance in Man. Autosomal and which is a n X-linked condition, or wit h orchi t is Catalogs of Autosomal Dominant, X -linked Phenotypes (3rd Edition) . The J ohns H op· secondary to radiation or mumps. kins Press, Baltimore and London, pp. 738. 4. Environmental agents (phenocopies) for ex Porter, I. H. (1968). Heredity an.d Disease. McGraw-Hill ample, in t he recessive condit ion of microce phaly Book Co mpany, New York, pp. 408. ll ing in a nd choriore tinopathy s imulated b y toxoplasmo Watson, W., and Carr, H . (1971). Genetic counse dermatology. Pediatr. Clin . North Am ., 18:757-771. sis.