REVIEW ARTICLE Egypt. J. Med. Hum. Genet. Vol. 10, No. 1, May, 2009 One , many

Rabah M. Shawky

Pediatrics Department, Ain Shams University ABSTRACT

Phenotype descriptions are valuable information right at the interface of medi- cine and . With the rapid advancement in the fi eld of , thou- sands of involved in human diseases have been cloned. It was expected that knowledge of would lead to consistent - cor- relations. The understanding of mechanisms underlying genotype-phenotype discrepancies is important, as it will move clinical genetics towards predictive medicine, allowing better selection of therapeutic strategies and individualized counseling of persons affected with genetic disorders.

Key Words: Corresponding Author: Gene, phenotype, mosaicism, epigenet- Rabah M. Shawky ics, . E-mail: [email protected]

INTRODUCTION

Phenotype descriptions are Mutations in different genes can lead valuable information right at to similar phenotype e.g., hereditary the interface of medicine and spherocytosis can be due to mutations biology. Their main value lies in the genes encoding for spectrin, in helping to dissect the rela- ankyrin3. In contrast, mutations in one tionships between diseases and gene could cause multiple phenotypes, genes1, in clinical application in as best illustrated in the case of lamin genetic counseling and prenatal A/C, whereby mutations can cause 13 diagnosis. The phenotype can be different diseases.4 thought of as a product of genes interacting with each other and With rapid advancement in the fi eld of with the environment. A con- genetics, thousands of genes involved cise defi nition of a gene, taking in human diseases have been cloned. It into account complex patterns was expected that knowledge of muta- of regulation and transcription, tions would lead to consistent genotype- genic conservation and non- phenotype correlations, clarifying why a coding RNA genes, has been given genetic change results in a particu- proposed by Gerstein et al.2 “A lar phenotype. However, genotype-phe- gene is a union of genomic se- notype correlation is often incomplete. quences encoding a coherent set Monogenic diseases provide the sim- of potentially overlapping func- plest models for studying genotype-phe- tional products”. notype relationships. The understanding Copyright: All rights reserved for The Egyptian Journal of Medical Human Genetics 1 One gene, many phenotypes of mechanisms underlying genotype- 2. Trinucleotide repeat expansion. phenotype discrepancies is important, 3. X- Inactivation. as it will move clinical genetics towards 4. Phenotypic heterogeneity due to predictive medicine, allowing better se- the interaction of at different lection of therapeutic strategies and in- loci. dividualized counseling of persons af- 5. Modifi er genes. fected with genetic disorders.5 6. . 7. Epigenetic mechanisms. Monogenic disease with many pheno- 8. Gene and environment. types: Ι. One gene, many mutations, many Ι. One gene, many mutations, many phenotypes. phenotypes: 1- Allelic heterogeneity: 1. Allelic heterogeneity. This phenomenon, whereby different 2. Non functional vs. partially func- mutations at the same locus result in tional/truncated gene product. different phenotypes. It is very interest- 3. Loss of function vs. gain of func- ing to know that mutations at a single tion. locus can lead to diseases with entirely 4. Pleiotropy. different clinical features. For example, mutations in the RET gene have been ΙΙ. One gene, one , many implicated in the etiology of Hirshprung phenotypes. disease as well as multiple endocrine neoplasia (MEN) Type 2. The underly- ΙΙΙ. Other mechanisms for phenotypic ing mechanism is either quantitative or heterogeneity of monogenic disease: qualitative change in the gene product. Some of the examples of allelic hetero- 1. Mosaicism ( gene dosage effect). geneity have been listed in (Table 1).5

Table 1: Selected examples of allelic heterogeneity. 5

Disease Gene Disease

Huler syndrome IDUA Scheie syndrome

Charcot-marie-tooth neuropathy PMP22 Hereditary neuropathy with pressure palsy

Hyperkalemic periodic paralysis SCN4A Paramyotonia congenita

Creutzfeldt-jacob disease PRNP Familial fatal insomnia

Pseudohypoparathyroidism IA GNAS1 Albright hereditary

Kennedy disease AR Androgen insensitivity

Cystic fi brosis CFTR Congenital bilateral absence of vas deference

Duchenne muscular dystrophy DMD Becker muscular dystrophy

Hirschsprung disease RET Multiple endocrine neoplasia type 2

2 Rabah M. Shawky 2- Non functional vs. partially func- gain of function mutations at the same tional/truncated gene product: site lead to a form of Duchenne and Becker muscular dys- ().8 trophies are caused by mutations in the dystrophin gene. Mutations that par- Also in the fi broblast growth factor re- tially inactivate the gene product cause ceptor 3 (FGFR3), point mutations in Becker muscular dystrophy (BMD), specifi c domains are associated with while mutations which completely inac- autosomal dominant dwarfi sm and tivate the gene product produce Duch- craniosynostosis syndromes such as enne muscular dystrophy (DMD). , (the most common form of skeletal 3- Loss of function vs. gain of func- dysplasia), severe achondroplasia with tion: developmental delay and acanthosis Phenotype resulting from reduction in nigricans (SADDAN), thanatophoric the amount of normal protein is called dysplasia, with loss of function, while gain of function acanthosis nigricans and Muenke coro- mutations, also known as neomorphic, nal craniosynostosis9. Several reports are characterized by the ability of the have demonstrated that these mutations mutant product to perform new lead to constitutive activation of the functions.6 receptors10. In contrast with the inhibi- tory role on bone growth, an oncogenic Example of that is RET gene which role for FGFR3 in human cancer has codes for a tyrosine kinase . emerged. Somatic activating mutations Loss of function mutations in RET gene in FGFR3 have been reported in mul- that lead to nonfunctional product or tiple myeloma and, more recently, in lower expression of RET gene give rise two epithelial malignancies, i.e. blad- to Hirschsprung disease. Gain of func- der- and cervix carcinomas11. Nearly all tion mutations at the same locus that mutations identifi ed in bladder tumours produce constitutively activated recep- are identical to the activating mutations tors lead to MEN Type 2. Similarly, loss responsible for , of function mutations at FGFR1 locus a lethal form of dwarfi sm.12 cause an autosomal dominant form of Kallman syndrome characterized by Several genes play important role anosmia and hypogonadotropic hypog- in embryogenesis have also been onadism, also cause lacrimo-auriculo- shown to play a role in causing cancer 13 dento-digital (LADD) syndrome7. The (Table 2).

Table 2: Genes that can cause both developmental anomalies and cancer.13

Gene Chromosome Developmental anomaly Cancer

PAX3 2q35 type 1 Alveolar rhabdomyosarcoma

KIT 4q12 Mast cell leukemia PTCH 9q22 Gorlin Basal cell carcinoma

RET 10p11 Hirschsprung MEN2A, MEN2B, thyroid carcinoma

WT1 11p13 Denys-drash Wilms tumer

3 One gene, many phenotypes 4- Pleiotropy: ΙΙ. One gene, one mutation, many The term pleiotropy comes from the phenotypes: Greek pleion, meaning “many” and tre- The phenomenon of allelic heteroge- pein, meaning “infl uencing”. Pleiotro- neity is not unexpected, as the gene py has been challenged by the remark- product may get differentially changed ably diverse syndromes that can result by the different mutations and so the from different mutations in the same phenotypes. More surprising is the fact gene, for example the LAMNA gene that individuals with similar genetic and X-linked fi lamin A gene. Mutations lesions can have signifi cantly differ- in LAMNA gene may cause Emery- ent clinical manifestations. This is well Dreifuss muscular dystrophy, a form of observed in autosomal dominant disor- limb girdle muscular dystrophy, a form ders, where ‘variable expressivity’ and of Charcot-Marie-Tooth disease, dilated ‘reduced ’ have been classi- cardiomyopathy, Dunnigan type familial cally described. Expressivity is defi ned partial lipodystrophy, mandibuloacral as the severity of the phenotype. When dysplasia and the very rare condition the severity of disease differs in people Hutchinson-Gilford progeria. Muta- with same genotype, the phenotype is tion in the fi lamin A gene have recently said to have variable expressivity. Pene- been implicated in the distinct, though trance is the proportion of persons with overlapping, X-linked dominant dys- a particular genotype who manifest the morphic conditions oto-palato-digital disease. The reduced penetrance leads syndrome, Melnick-Needles syndrome to ‘skipping of generation’. Neurofi - and frontometaphyseal dysplasia and bromatosis Type 1(NF1) is character- periventricular nodular hetertopia.13 ized by extreme clinical variability, not only between unrelated individuals and Antagonistic pleiotropy refers to the ex- among affected individuals within a pression of a gene resulting in multiple single family but even within a single competing effects, some benefi cial but individual with NF1 at different times others detrimental to the organism. This in life. The mutation in the NF1 gene is central to a theory of aging fi rst de- can produce different lesions in differ- veloped by Williams14. Williams14, sug- ent tissues such as cafe-au-lait spots, gested that some genes responsible for neurofi broma, iris hamartoma, skeletal increased fi tness in the younger, fertile abnormalities or mental retardation. organism contribute to decreased fi tness Each of these pleiotropic effects can later in life. have varying severity among the affect- ed family members (variable expressiv- One such example in male humans is ity). The mechanisms underlying such the gene for the hormone testosterone. clinical variations are often unclear. It In youth, testosterone has positive ef- is supposed to be the result of the modi- fects including reproductive fi tness but, fying effects of other genes, as well as later in life, there are negative effects due to interaction with environmental such as increased susceptibility to pros- factors.5 tate cancer. Another example is the p53 gene which suppresses cancer, but also ΙΙΙ. Other mechanisms for phenotypic suppresses stem cells which replenish heterogeneity of monogenic disease: worn-out tissue.15 There are a variety of other mechanisms

4 Rabah M. Shawky that may be responsible for generating of Pearson syndrome (sideroblastic phenotypic diversity of diseases that anemia, exocrine pancreatic dysfunc- are encoded at a single locus, Some of tion) and progressive external ophthal- these, which have been loosely labelled moplegia. The different phenotypes epigenetic, are understood, at least from the same deletion are due to tissue in principle, although the molecular distribution of the defect. If the defect mechanisms involved have not been es- is present in mitochondria of all tissues, tablished and the prediction of the phe- the phenotype is Kearns-Sayre syn- notype from the underlying genotype drome. In Pearson syndrome, the defect may be extremely diffi cult.16 is localized mainly to the hematopoietic tissue, while the defect is confi ned to 1- Mosaicism (gene dosage effect): the skeletal tissues in progressive exter- Mosaicism is the existence of two cell nal ophthalmoplegia17. Another striking lines with different genetic constitution example of phenotypic diversity arising that have been derived from a single zy- from mosaicism is the androgen insen- gote. sitivity syndrome (AIS). Androgen in- sensitivity syndrome is the major cause The phenotypic severity is determined of male pseudohermaphroditism. It is by the proportion of cells carrying the an X-linked disorder caused by muta- mutation. This is best exemplifi ed in tions in androgen receptor (AR) gene. mitochondrial disorders. There are thou- Androgen insensitivity syndrome can sands of mitochondrial DNA (mtDNA) be subdivided into three highly variable molecules in a cell. When a mutation oc- phenotypes: complete AIS, when the curs in the mtDNA, it is at fi rst present affected persons have female external in only one of the mtDNA molecules. genitalia; partial AIS, when the genita- At cell division, the mtDNA molecules lia are ambiguous and mild AIS, when replicate and sort randomly among the the affected individuals have normal daughter cells. Each daughter cell may male external genitalia. In a number of receive very different proportions of cases, identical mutations have resulted mitochondria carrying normal and mu- in signifi cantly different phenotypes. tant mtDNA. The phenotype will de- This is due to somatic mosaicism18. The pend upon three factors: The relative co-expression of wild allele shifts the abundance of mutant mtDNA (hetero- AIS subtype to a higher degree of viril- plasmy), the tissue distribution of the ization than expected from the mutant mutant mtDNAs and the vulnerabil- allele alone.5 ity of each tissue to impaired oxidative metabolism (threshold effect). Thus, re- 2- Trinucleotide repeat expansion: duced penetrance, variable expression Also known as triplet repeat expansion, and pleiotropy are typical features of is the DNA mutation responsible for kindred with mitochondrial disorders. causing any type of disorder categorized For example, a deletion of 4977 bp of as a trinucleotide repeat disorder. These mtDNA is commonly encountered in are labelled in dynamical genetics as Kearns-Sayre syndrome (characterized dynamic mutations19. At least 12 neu- by the triad of pigmentary retinopathy, rological diseases are known to result external ophthalmoplegia and onset be- from expansion of CTG, CGG, CAG fore the age of 20 years). The same de- or GAA repeats. Fragile-X syndrome, letion has also been identifi ed in cases which is a common cause of mental re- 5 One gene, many phenotypes tardation in males, is a good example of seems to accurately predict age of onset how phenotypic, heterogeneity can be and the way the disease will progress in generated by expansion of regions con- an individual, based on the number of taining trinucleotide repeats, in normal repeats of a genetic mutation20. Over- individuals, a DNA segment at Xq27,3 all these conditions show considerable contains between six and 60 copies of phenotypic heterogenity This is refl ect- the repeat CGG, in some persons, the ed at the molecular level, where there number is increased to between 60 and is a wide variation in the extension of 200. In this case, the disorder is clini- the length of the repeats required to cally silent; premutations of this kind produce an abnormal phenotype, not all are characteristic of normal-transmit- diseases are associated with a premuta- ting males and some mentally normal tion length and the relationship between female carriers. Full mutations, which the expansion of trinucleotide repeats arise in the offspring of pre-mutation and the causation of the disease is not carriers, consist of many hundreds or clear. In some cases, those in which the thousands of copies, of the repeat and repeats involve promoters, it is thought lead to the full expression of the clini- that methylation of the promoter region cal phenotype. Heterozygous carriers lead to gene silencing while in those have an extremely variable phenotype: that involve CAG repeats it is thought Approximately 50% of females carry- that polyglutamine expansion may play ing the full mutation, how some mental a role. But what is clear is that genotyp- impairment although those who carry a ic instability of this type is responsible pre-mutation are usually normal. Simi- for neurodegenerative disorders with larly, female carriers may or may not widely differing phenotypes.16 show some of the somatic changes as- sociated with the disease in males. Al- 3- X- Inactivation: though X inactivation may be partly X-inactivation in females is usually responsible, this does not seem to be random, because of that female carriers the whole story. Huntington’s disease, for a particular X-linked trait are in ef- another neurodegenerative disorder, fect, mosaics, with each cell population also shows considerable phenotypic functionally hemizygous for a particu- heterogeneity, particularly with respect lar trait. Hence carriers would be ex- to age of onset and rate of progression, pected to produce approximately half At the 5`- region of the locus involved of an abnormal gene product or express there is a CAG repeat sequence, which about the same amount of a product. ranges from ten to 30 copies in normal However, because X inactivation oc- individuals and which is expanded to curs early during embryogenesis, there beyond 35 copies in patients with Hun- is wide variation in the expression of tington’s disease, there appears to be X-linked mutant genes in females; con- some relationship between the length of siderable skewing of the distribution the repeats and age of onset. Remark- of values is encountered. Interestingly, ably, the juvenile onset of cases shows there is a high frequency of discor- a preponderance of paternal trans- dant phenotypes, among twins with X- mission16. In 2007 a new disease model linked diseases21, this may be because was produced to explain the progression X inac tivation preceeds twinning and of Huntington’s Disease and similar non-randomness refl ects asymmetri- trinucleotide repeat disorders, which, cal splitting of the inner cell mass, 6 Rabah M. Shawky furthermore, it seems likely that some heterozygotes for a specifi c peripherin- X-linked disorders may have a deleteri- RDS gene muta tion and a muta tion in a ous effect on cell function during early second gene, ROM1. It is thought that embryogenesis, a phenomenon that may the products of these two loci. which lead to extreme skewing of the distribu- are on different chromosome, interact tion of cell populations. The situation non-convalently in the rim region of the is further complicated by the fact that photoreceptor outer segment disc mem- not all parts of the X chromosome are brane. Persons heterozygous for only inactivated. These different issues make one of these mutations have no symp- for considerable hetero geneity in the toms. expression of mutant gene’s in female carriers for X-linked disorders. There Another condition that shows marked is increasing evidence that negative phenotypic heterogeneity is inher- selection may be a major factor for the ited porphyria cutanea tarda. in which skewed distribution of cell populations heterozygotes are predisposed to pho- in female carriers. For example, Cole- tosensitive cutaneous lesions. The phe- 22 notype seems to be exacerbated by a man et al. described a female with the variety of enviromental factors, includ- genes for both incontinentia pigmenti ing iron overload and alcohol abuse. and haemophilia A. It appeared that the The condition results from a defi ciency presence of the gene for incontinentia of uroporphyrinogen decarboxylase pigmenti on an X chromosome had un- (URO-D). Not all patients with muta- masked the factor VIII gene mutation tions at the gene that encodes URO-D on the other chromosome, presumably are symptomatic. Recently it has been by negative selection of the former. found that there is an increased frequen- Another example is female carriers of cy of the alleles of the haemochromato- hemophilia and DMD may occasion- sis gene, notably C282Y AND H63D, ally show mild or even full expression in both Argentinian and Italian patients with porphyria culanea tarda. Since the of the disease. This is due to nonran- haemochromatosis alleles are associ- dom inactivation of X chromosome, as ated with increased iron absorption and by chance, most of the X chromosomes iron overload and because iron loading carrying the normal allele get inactivat- exacerbates porphyria cutanea tarda, ed resulting in clinical expression of the it seems likely that this is another ex- disease.5 ample of the deleterious interaction of two alleles, in this case with completely 4- Phenotypic heterogeneity due to different functions.24,25 the interaction of alleles at different loci: 5- Modifi er genes: Retinitis pigmentosa is the name given A modifi er gene is defi ned as an inher- to a set of inherited degeneration of the ited genetic variation that affects the phenotypic expression of another gene. retina. This condition is very heteroge- It can affect the pleiotropy, penetrance neous, both clinically and with respect or expressivity of the disease. Depend- to inheritance. It is X- linked, however ing upon the nature of modifying effect, both autosomal dominant and recessive modifi er genes might cause more severe forms have been described. Kajiwara phenotypes, less severe phenotypes, et al.23 reported three families in which novel phenotypes or wild-type (normal) a form of retinitis pigmentosa segre- phenotypes.26 gated; affected individuals were double 7 One gene, many phenotypes A- Modifi er causing less severe (re- A- Duchenne muscular dystrophy and duced) phenotype of Beta thalassemia. BMD are caused by mutations in the The severity of anemia in beta thalas- dystrophin gene. Duchenne muscular semia refl ects the degree of globin dystrophy is a severe muscle-wasting chain imbalance. The excess of alpha disease arising from defects in the globin chain precipitates in red cell pre- dystrophin gene, typically nonsense cursors leading to ineffective erythro- or frameshift mutations that preclude poiesis. This imbalance can be geneti- the synthesis of a functional protein. cally modifi ed by two factors-variation Becker muscular dystrophy generally in amount of gamma globin response arises from in-frame deletions that al- and alpha globin chain production27. low synthesis of a shorter but still semi- The beta thalassemia patients who co- functional protein. But, nonsense muta- inherit alpha globin gene deletions will tions which should cause DMD have have less redundant alpha globin chains been reported in BMD. This is due to and tend to have less severe phenotype. alternative mRNA splicing- skipping of Similarly, increased synthesis of gam- the affected exon leads to removal of ma globin chain will reduce the disease the nonsense mutation from the dystro- severity by increasing HbF level. The phin mRNA. This results in production gamma globin response is also geneti- of partially functional dystrophin and cally determined. There are many other BMD phenotype. loci that are not linked to the beta globin gene but modify HbF response. Linkage B- Cystic fi brosis is an autosomal re- studies have mapped these loci to three cessive disorder. The genotype delta regions of the genome-chromosome F508/R117H can lead to either severe 6q23, 8q11 and Xp22.28 phenotype of cystic fi brosis leading to respiratory failure or the milder pheno- B- Modifiers causing more type, in which the only manifestation is severe (enhanced) phenotype congenital bilateral absence of vas def- The severity of anemia in beta thalas- erens (CBAVD). The CFTR gene has semia depends on the degree of globin two intron 8 variants. One is associated chain imbalance. It is an autosomal re- with effi cient mRNA splicing, while the cessive condition. The heterozygotes other causes ineffi cient splicing. The for beta thalassemia mutations are clini- R117H allele is capable of producing cally asymptomatic as the degree of im- partially functional protein. The R117H balance is insignifi cant. But, the coin- allele associated with effi cient splicing heritance of extra alpha globin genes leads to production of some amount of (alpha triplication) increases the imbal- partially functional protein and hence ance. This leads to symptomatic disease milder phenotype (CBAVD). On the in heterozygotes, sometimes manifest- other hand, severe phenotype results if ing as ‘intermedia’ phenotype.29 the intron 8 variant causes ineffi cient splicing and production of nonfunction- 6- Alternative splicing: al protein.30 Alternative mRNA splicing is another mechanism responsible for different 7- Epigenetic mechanisms: expression of a similar genotype. Two The term refers to changes illustrative examples are given below. in caused by envi-

8 Rabah M. Shawky ronmental factors, not by changes in B- Transgenerational epigenetic ob- the underlying DNA sequence. These servations: changes may remain through cell divi- Marcus Pembrey and colleagues also sions for the remainder of the cell’s life. observed that the paternal (but not ma- Sometimes the changes last for multiple ternal) grandsons of Swedish boys who generations31. The Greek prefi x epi- in were exposed to famine in the 19th cen- epigenetics implies features that are “on tury were less likely to die of cardiovas- top of” or “in addition to” genetics; thus cular disease; if food was plentiful then epigenetic traits exist on top of or in ad- diabetes mortality in the grandchildren dition to the traditional molecular basis increased, suggesting that this was a for inheritance. Epigenetic phenomena transgenerational epigenetic inheri- modulate when and at what level genes tance.33 are expressed. Thus, the expression of a mutation also depends upon the activity 8- Gene and environment: state of the locus carrying it; the mere Virtually all human diseases result from presence of a genetic defect may not be the complex interplay of genetic sus- enough for clinical expression. Epige- ceptibility factors and modifi able envi- netic effects in humans include the fol- ronmental factors. This is most obvious lowing: in the context of common illnesses such as diabetes, coronary artery disease or A- Genomic imprinting and related cancer. But, environmental factors play disorders: a signifi cant role in the expression of The term “imprinted gene” refers to monogenic disorders too. For example, genes whose expression is conditioned inherited metabolic disorders manifest by their parental origin.32 when there is introduction of the sub- strate for which the metabolism is de- The expression of a gene depends upon fective. Similar genetic defects may the parent who passed on the gene. have different phenotypes if the envi- For example, two different diseases ronmental factors are not similar.5 - Prader-Willi syndrome and Angelman syndrome - are due to deletion of the REFERENCES same part of chromosome 15. When the deletion involves the chromosome 15 1. Groth P, Weiss B, Pohlenz HD, Leser inherited from the father, the child has U. Mining phenotypes for gene func- Prader-Willi syndrome, but when the tion prediction. BMC Bioinformatics deletion involves the chromosome 15 2008; 9: 136. inherited from the mother, the child has Angelman syndrome. This is a striking 2. Gerstein MB, Bruce C, Rozowsky example of how the parental origin of JS, Zheng D, Du J, Korbel JO, et al. a genetic defect infl uences the clinical What is a gene, post-ENCODE? His- phenotype. Beckwith-Wiedemann syn- tory and updated defi nition. Genome drome is also associated with genomic Res. 2007; 17(6): 669-81. imprinting, often caused by abnormali- ties in maternal genomic imprinting of 3. Bolton Maggs PH. Hereditary sphero- a region on chromosome 11. cytosis; New guidelines. Arch. Dis.

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