Lessons from studying monogenic disease for common disease

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Lessons from studying monogenic disease for common disease
Human Molecular Genetics, 2006, Vol. 15, Review Issue 1
doi:10.1093/hmg/ddl060
R67–R74
Lessons from studying monogenic disease
for common disease
Leena Peltonen1,2,3,*, Markus Perola1,2, Jussi Naukkarinen1,2 and Aarno Palotie3,4
1
Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland, 2Department of Medical
Genetics and Program for Molecular Medicine, University of Helsinki, Finland, 3The Broad Institute of MIT and
Harvard, Boston, MA and 4Finnish Genome Center, Department of Clinical Chemistry and Program for Molecular
Medicine, University of Helsinki, Finland
Received March 2, 2006; Revised and Accepted March 9, 2006
The prevailing paradigm for common disease emphasizes the
role of common variants predisposing to various rampant
health problems, and these genetic risk profiles interact with
environmental and life style risk factors triggering the
disease process and modifying its progress. However, most
of what we know about the molecular background of
common diseases is in fact based on what we have learned
from rare familial forms of these traits. Further, often the
mutations identified in even more rare monogenic diseases
sharing some trait components with common diseases have
exposed critical new pathways involved in the molecular
pathogenesis of common health problems. In this review, we
aim to exemplify some of the lessons learned from rare
Mendelian forms of diseases that have significantly contributed to our understanding of the genetic background of
common diseases and their trait components.
MENDELIAN CASES OF COMPLEX TRAITS
Identification and characterization of different mutations in
Mendelian variants of common traits have been extremely
successful with improved accuracy of genome-wide analyses
provided by the Genome Project. These, usually rare single
gene disorders masquerade a multifactorial trait in their clinical phenotype, but careful data collection of family history
(Mendelian segregation in a family), and detailed clinical
examination (the cases are exceptionally severe or deviate
otherwise from the typical disease cases) have revealed the
exceptionally strong genetic character of the trait. Typically,
linkage and association studies in such families have guided
to a gene responsible for the disease in those particular
families. Usually the mutations identified have been nearly
family-specific and their value in clinical diagnosis has
remained modest. Neither have they explained the majority
of cases at the population level. However, by studying these
‘human allelic knockouts’ a unique view into the pathophysiology involved has been obtained. Table 1 provides a list
of examples for which rare Mendelian forms of common diseases have resulted in the identification of disease genes and
subsequent functional studies have evidenced their relevance
for common traits. Informative examples among them
include familial Alzheimer’s disease (AD), MODY(s) (maturity onset diabetes of the young), familial combined hyperlipidemia (FCHL) and rare familial forms of epilepsies and
migraine. These disorders, characterized by their distinct heritability have opened new avenues in further evaluation of the
more common forms of dementia, diabetes, dyslipidemias and
common forms of epilepsy and migraine.
Familial ADs
If only judged by the number of publications, most genetic
studies on AD have considered one genetic polymorphism,
the Apolipoprotein E epsilon 2/3/4 variant as a major risk
determinant. However, most insight into the molecular pathogenesis and events resulting in characteristic tissue pathology
has been produced by studies of the early onset familial forms
of the disease, showing classical Mendelian inheritance in
exceptional dementia families. In Caucasians, about 1 – 6%
of all AD is early onset (,60 years) and ~60% of this
early-onset AD is familial, with 13% inherited in an autosomal
dominant manner (1,2). The AD mutations identified in these
families exposed genes encoding presenilins and the amyloid
precursor protein (APP), the common denominator being
that they all alter APP processing in the brain. Together, variations in these three genes cover ~70% of early-onset AD
mutations in the French (2). There is most likely considerable
population based variance in these frequencies, but all in all,
these rare variants probably explain only about 1– 2% of AD
cases. That said, the accumulated knowledge of the critical
metabolic pathway, and the emerging understanding that one
*To whom correspondence should be addressed at: National Public Health Institute, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland.
Tel: þ358 947448393; Fax: þ358 947448480; Email: [email protected]
# The Author 2006. Published by Oxford University Press. All rights reserved.
For Permissions, please email: [email protected]
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Table 1. Examples of Mendelian traits that have provided new understanding of the background of common diseases
Common trait
Monogenic, Mendelian form
Gene/gene group mutated
Impact for common trait
Psychiatric disorders
Familial autism, rare syndromes
translocations
Robo1, FOXP2, DISC1, neuroligins
Alzheimer’s disease
Familial early onset forms
Presenilins, APP
Epilepsy
Familial epilepsies
Headache disorders
Familial hemiplegic migraine
Cardiac arrhythmias
Long QT syndrome
Dyslipidemias
Tangier’s disease, low HDL, familial
hyperlipidemias
Hypertension
Rare syndromes causing hypo- or
hypertension
Obesity
Rare syndromes rodent models
Ion channels, e.g. SCN1A, SCN1B,
KCNQ2, KCNQ3
Ion channels, CACNA1A, SCN1A,
ATP1A2
Ion channels, e.g. KCNQ1, HERG,
SCN5A, KCNE1, KCNE2
ABCA1 transporter USF1 LDL receptor
APOB, ApoA1, LCAT, ABCG5,
ABCG8, ARH
Genes associated with renal salt balance
e.g. ENaC, mineralocorticoid receptor
gene
Brain- and adipose tissue-derived
hormones, leptin receptor, MC4R,
Lipin
Suggestive role established in various study
samples Functional data in cellular
systems
Molecular mechanism behind amyloid
plaques
Strong hypothesis for role of ion channels
and related pathways
Strong hypothesis for role of ion channels
and related pathways
Suggestive background for unexplained
sudden death
Functional data on the effect of cellular
cholesterol transport and metabolism
Diabetes
Familial forms, MODY
Glucokinase transcription factors
Autoimmune diseases
APECED, ALPS, IPEX
Transcription regulators, Fas-receptors
and their ligands, caspases
Several genes also associated with essential
hypertension. Pinpointing basic
mechanisms of blood pressure regulation
Importance of brain- and adipose
tissue-derived hormones and the hormonal
cross-talk between fat tissue and the
hypothalamus-hypophysis axis
Lessons of mechanisms resulting in beta cell
dysfunction
The critical role of central tolerance in
autoimmunity
Novel genes and pathways identified through the study of exceptional families segregating a disease in Mendelian fashion have played a decisive role
in the characterization of more common forms of diseases with milder phenotypes. This table attempts to summarize some of the best examples. A
complete list of references is available at http://www.genome.helsinki.fi/publications/peltonen/table2.
metabolic pathway is shared by all the familial forms of the
disease cannot be surpassed in importance when considering
the etiology of the complex form of the trait. The understanding of rare Mendelian forms of AD has even paved the way for
new hypotheses concerning the etiology and pathogenesis of
neurodegenerative diseases more generally. In AD, mutations
in the APP or presenilins results in disease by a mechanism
that involves the deposition in the brain, of abnormally processed amyloid. This is also seen in other neurodegenerative
diseases such as Creuzfeldt –Jakob disease and Parkinson’s
disease (3).
Familial diabetes, MODY
MODY represents a rare familial form of common diabetes
and accounts for 2– 5% of diabetes mellitus (DM) in most
western societies (4), for ,5% of DM in childhood and
0.5 –1% of non-insulin dependent DM in most Caucasian
(European) populations (5). All known forms are characterized by an autosomal dominant inheritance and the age of
onset in early adulthood (usually before 25 years of age) (6).
Currently six mutated genes for MODY are known, whereas
some forms of MODY remain un-characterized at the molecular level (7). Mutations in these six genes account for 80% of
European and 20% of Japanese with clinical MODY. The
mildest form of MODY is caused by mutations in the glucokinase gene, while five other more severe forms are caused
by mutations in genes encoding various transcription factors.
Identification of variant MODY genes has provided insight
into the development of B-cell dysfunction in the pancreas
paving way towards understanding of the molecular processes
behind more common forms of DM as well. The fact that all
MODY genes are critical for development and function of
the pancreatic beta cells has not only produced a new paradigm for the genetic studies of more common forms of
diabetes—but also opened the way for understanding the
pathophysiology behind different forms of diabetes (7). It
became evident that MODY is not a single entity but presents
clinical, metabolic and genetic heterogeneity, the phenotype
correlating with the causative mutations. Further, some genetically specified forms of MODY are responsive to specific
treatments underlining the importance of careful molecular
dissection of the trait. (8). These lessons have definitively
molded our thinking of the molecular background and its
significance for phenotype variations in common forms of
diabetes.
Familial dyslipidemias
FCHL is a combination of heterogenous dyslipidemias segregating in families and predisposing affected individuals to
early-onset cardiovascular disease. FCHL is considered the
most common familial dyslipidemia in Caucasian populations
and estimated to be responsible for ~10% of early-onset coronary heart disease. Though the syndrome was described in the
early 19700 s among survivors of early myocardial infarcts,
the first FCHL-associated gene was described only recently
in Finnish FCHL families (9). This gene on 1q encodes the
upstream stimulatory factor-1 (USF1), a ubiquitous transcription factor regulating numerous genes participating in lipid
Human Molecular Genetics, 2006, Vol. 15, Review Issue 1
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Figure 1. Example of a gene identified in rare families and it’s potential significance for trait components of common diseases, transcription factor USF1: the
expression of numerous genes involved in lipid and glucose metabolism must be dynamic to meet the changing requirements of our physiology. USFs activate
and repress the expression of many of these genes according to hormonal and metabolic cues such as insulin and glucose by binding an E-box promoter sequence
upstream of its target genes. In the presence of insulin, the USF1/USF2 dimer becomes phosphorylated, precluding its binding the E-box and results in decreased
expression of the target gene (15). Variation in the function of USF1 has potentially far reaching effects on lipid and glucose metabolism, features relevant to a
number of common dyslipidemias and trait components of the metabolic syndrome.
and glucose metabolism (10,11) (Fig. 1). The involvement of
the allelic variants of USF1 in dyslipidemias and trait components of the metabolic syndrome has been replicated in
different populations and study samples ascertained for these
traits (9,12 –15). The identified risk alleles do not seem to
represent mutations breaking the protein, but rather variants
putatively affecting the transcript level of the gene itself.
Importantly, allelic variants of USF1 seem to contribute to
cardiovascular disease risk also at the population level (16).
The function of USF1 and especially the number of highly relevant downstream genes regulated by USF1 makes this gene,
initially identified in rare exceptional families with combined
hyperlipidemia, an attractive candidate for trait components of
the metabolic syndrome.
Familial epilepsies and atypical migraines
Epilepsies and migraine are two paroxysmal CNS disorders in
which major efforts have been invested in studies of
Mendelian trait variants as models to unravel the pathogenic
mechanisms involved in the more complex forms of the
trait. Similar to many Mendelian forms of common traits
even within exceptional multi-case families, the range of the
phenotype is broad: some of the affected family members
have an extreme clinical phenotype, some have phenotypes
indistinguishable from more common forms of migraine or
epilepsy. Thus, although these familial forms represent only
a few percentages of the overall prevalence, they have been
considered attractive models in identifying the underlying
metabolic pathways. Interestingly, they all seem to fall
under the umbrella of channelopathies. In monogenic epilepsies alterations in potassium, sodium and chloride channels
as well as GABA and acetylcholine receptors have been
described (17). In the case of Mendelian forms of migraine,
Famial Hemiplegic Migraine (FHM), alterations in calcium
and potassium channel genes and in an intracellular Naþ/
Kþ -ATPase (18,19) have been described. The apparent,
well documented central role of alterations in ion channels
in the Mendelian forms of these two traits has stimulated the
hypothesis that susceptibility to more common forms of
migraine and idiopathic epilepsy could also, at least partially,
be explained by altered functions of neuronal ion channels. In
the case of epilepsy, the calcium channel gene CACNA1H and
the GABARD gene have been associated with common forms
of idiopathic epilepsy; CACNA1H with idiopathic generalized
epilepsy and childhood absence epilepsy, GABARD with
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idiopathic generalized epilepsy and generalized epilepsy with
febrile seizure plus (17). In the case of common forms of
migraine, good evidence for the involvement of these genes
in trait susceptibility has not yet been reported, although it
remains a strong hypothesis.
RARE MONOGENIC DISEASES REVEALING
CRITICAL PATHWAYS
Genes of exceptional obesity
Obesity, a dramatically increasing plague of global societies
has been traditionally considered to be largely environmental
or life-style dependent. However, the lessons from experimental animals and extremely rare monogenic syndromes in
humans have pinpointed the critical importance of brainand adipose tissue-derived hormones and the hormonal crosstalk between fat tissue and the hypothalamus-hypophysis axis.
Different monogenic forms of severe obesity have been found
to be caused by mutations in specific genes encoding hormones, hormone receptors or their regulatory molecules
(20). The pioneer work on leptin, initially identified on the
basis of the rodent models and progressing to direct demonstration of the lack of leptin in human patients with syndromic
obesity has provided undeniable evidence for the tremendous
impact of normal leptin levels on human fat mass and opened
new avenues for novel treatment strategies of morbid obesity.
Mutations identified in these rare syndromes have not proved
to be common among obese individuals at the population
level, with a notable exception of one melanocortin receptor
gene, MC4R, seem to be important for obesity; up to 4% of
obese children are estimated to carry mutations of this gene
(20) and some evidence exist that different allelic forms of
this gene associated with a higher body mass index at the
level of general population (21). Findings in extremely rare
forms of obesity, often represented by only a handful of children or families have thus highlighted critical pathways for the
control of human fat tissue and its normal metabolism.
Rare syndromes with hypertension
Most of our understanding of the molecular pathogenesis of
hypertension emerges from a systematic characterization of
the mutations in rare monogenic diseases, characterized by
high blood pressure. This tedious work has been of paramount
importance, because although the environmental and life-style
risk factors of common hypertension are reasonably well
defined (e.g. salt intake, age, gender and body mass index),
the primary molecular defects and triggering cascades
behind essential hypertension have remained obscure. It is
the rare monogenic diseases that have provided an avenue
for identification of critical molecules behind abnormally elevated blood pressure. About 20 different single gene disorders
that cause either hyper or hypotension have been identified
thus far. Markedly, as in AD, all Mendelian forms identified
thus far can be considered to represent ‘the final common
pathway;’ they all interfere with the normal function of the
critical molecules involved in the regulation of salt balance
of the body by the kidneys (22).
The epithelial sodium channel (ENaC), functioning in the
cortical collection tubule of the nephron plays a crucial role
in several forms of monogenic hyper or hypotension.
Gain-of-function mutations in the beta and gamma subunits
of ENaC cause a rare Liddle’s syndrome with severe hypertension (23). Loss-of-function mutations in any of the three
subunits of ENaC cause an autosomal recessive syndrome
with hypotension (pseudohypoaldosteronism type I, OMIM
264350). Thus, dysfunctions of all three subunits of this
sodium channel result in human diseases, either in hyper or
hypotension. Another set of rare syndromes, resulting from
mutations in the mineralocorticoid receptor gene (24) affect
the activity of this receptor, an important regulator of ENaC
activity (25). Such studies of rare Mendelian disorders with
dysfunctions of blood pressure regulation have highlighted
the crucial importance of a set of molecules functioning in
Henle’s loop and regulating salt balance under the control of
renin-angiotensin-aldosterone system has advanced our understanding of the molecular pathogenesis of the more common
essential hypertension as well as provided new target molecules for pharmaceutical industry (25).
Genes behind monogenic autoimmunity
Concerning the complex background of human autoimmune
disorders, rare monogenic diseases have provided critical
clues of the molecular pathogenesis involved. The investigation of these diseases have identified molecules of the
immune system that would have remained uncharacterized
without the detailed clinical description of exceptional
families that served as a catalyst for further molecular work.
A good example is APECED, a rare monogenic autoimmune
disease, enriched in Finland and in some other isolated populations, such as the Iranian Jews. Isolation of the mutated gene
Aire (autoimmune regulator) by classical positional cloning in
Finnish families and subsequent production of the knock out
mouse model resulted in the identification of a novel critical
molecule that regulates the ectopic expression of a subset of
autoantigens, characteristic for peripheral tissues, during the
fetal period in thymus (26). Further studies have implied
that this process, critical for the so-called central tolerance,
is in the crucial position for the development of late-onset
common autoimmune diseases like type I diabetes and have
provided new avenues for production of accurate animal
models and future therapy trials for these common traits (27).
SAME GENE, DIFFERENT MUTATIONS IN RARE
AND COMMON FORMS OF DISEASE
Characteristic of early onset Mendelian traits with severe
phenotypes, the causative mutations generally result in
amino acid alterations and truncated protein products and
their consequences for molecular functions are relatively
easy to predict. Most probably the genetic predisposition
for late-onset common traits is more often associated with
variants in non-coding areas, likely affecting the regulation
of transcription, tissue specific splicing or with variants
that carry their effect by some other, more subtle mechanisms during the life span of an individual. Although the
Human Molecular Genetics, 2006, Vol. 15, Review Issue 1
number of well established variants of specific genes associated with any common trait is still limited, they seem to
support an overall hypothesis that a large fraction of
common predisposing variants do not alter the primary
protein structure.
A good example of the differing effects of different type of
mutations of the same gene is provided by the case of the two
forms of lactose intolerance. Homozygote nonsense or truncating mutations breaking the synthesized polypeptide and resulting in complete absence of the intestinal lactase enzyme were
recently described to cause congenital lactase deficiency—a
severe gastrointestinal disorder characterized by watery diarrhea in infants fed with breast milk or other lactose-containing
formulas (28). Interestingly, another variant located 14 kb
upstream from the lactase gene has been established resulting
in an adult type lactose intolerance (lactase non-persistence),
causing much milder late-onset symptoms and being
common in most global populations (29). This variant interferes with a cis regulatory element capable of enhancing
transcriptional activation of the lactase promoter, which is
characteristically down-regulated in humans after weaning
(30). The lesson obtained might hold also for other genes in
which mutations resulting in a broken polypeptide produce a
rare early-onset trait, whereas causative variants behind
common late-onset trait might well be identified in non-coding
and regulatory regions of the same gene, posing a much harder
challenge for researchers tracing those variants.
A somewhat different example involves variants in the
ATP-binding cassette transporter A1 (ABCA1), associated
with near absence of plasma HDL-cholesterol (HDL-C).
Using linkage and positional candidate gene strategies,
mutations in the ABCA1 gene were demonstrated to cause
Tangier disease—a rare autosomal recessive disease of low
HDL-C, leading to the severe deposition of cholesteryl
esters in the reticulo-endothelial system in organs like spleen
(31,32). Tangier patients have truncating mutations in both
alleles of the ABCA1 gene. Interestingly, heterozygote
family members showed decreased HDL-C plasma levels
without other symptoms of Tangier disease. This stimulated
a hypothesis that variants of ABCA1 and other genes in the
same pathway might be associated with HDL-C plasma
levels also in the general population. There is still a lack of
studies that would provide a comprehensive coverage of
ABCA1 variations and their potential association with
HDL-C levels in the general population. However, two extensive studies have addressed this question. The promoter and
coding region variants of the ABCA1 gene were screened
for in the lowest and highest 1% HDL-C level samples from
the general population of over 9000 Danes and one common
non-synonymous SNP was associated with extremes of the
HDL-C distribution (33). In another study in two population
cohorts from Canada and US, the coding regions of three
genes, associated with Mendelian forms of low HDL-C
(ABCA1, APOA1 and LCAT ) were sequenced. Interestingly
one out of six individuals with HDL-C levels below the fifth
percentile had a rare functional mutation either in ABCA1 or
APOA1(34). Although not conclusive, these two studies
support the hypothesis that indeed variants of the genes,
earlier associated with rare monogenic or Mendelian trait
also contribute to the HDL-C level in the general population.
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Finally, for some established examples of distinct
Mendelian mutations, common at the population level, the
penetrance is so variable that the genotype – phenotype correlation is almost as complicated as in truly complex traits. First,
the disease proved to be more heterogeneous than expected,
the research of rare families has exposed a total of six genes
and has significantly contributed to our understanding of
iron homeostasis. Secondly, although one mutation explains
most of the cases, a C282Y mutation in the HFE gene,
many puzzling questions prevail concerning the impact of
the mutation, found in a homozygote form in 64– 100% of
cases (35). In the European population, the allele frequency
of the C282Y variant ranges from 2.6% to 28%, increasing
from south-east to north-west. Yet, the prevalence of hereditary hemochromatosis in most populations is ,1%. Three prospective studies have followed C282Y homozygotes over time
(36 –38). Interestingly, these studies did not consistently identify increasing transferrin saturation and serum ferritin levels
over time and did not demonstrate a clear link to the overt
clinical manifestation of hereditary hemochromatosis. Thus,
although in clinical manifest hemachromatosis patients the
association to the HFE gene is evident, on the individual
level, in asymptomatic subjects, a heterozygote C282Y
mutation has a relatively low predictive value of a clinically
manifest disease. What the final triggering factors are is still
unclear, but environmental components, such as excessive
alcohol consumption surely explain a portion of the phenotypical heterogeneity (39). The role of other hemochromatosis
genes (e.g. HAMP and HJV ) affecting the penetrance of the
HFE homozygotes has been demonstrated in some cases,
providing an interesting scenario of a potential interplay of
multiple genes affecting iron metabolisms and finally the
penetrance of the C282Y mutation. Such lessons emerging
from studies of many monogenic diseases are highly useful
for our thinking of the factors affecting clinical phenotype
of common diseases.
RARE GENOMIC REARRANGEMENTS GUIDING
TO PATHWAYS BEHIND COMPLEX TRAITS
A number of genes causing Mendelian disorders have been
identified based on the gross chromosomal alterations such
as translocations that have guided to the mutated gene. Their
usefulness in mapping complex traits has not been fully utilized in a systematic genome-wide manner, but some successes exist. Chromosomal translocations have guided to
genes associated with speech and language disorders
(40,41). The emerging understanding of the complexity of
the genome landscape, its submicroscopic changes and polymorphisms pave the way for further insight into the association between genomic rearrangements and complex
phenotypes. Thus, not only classic chromosomal translocations but also other smaller genome rearrangements, such as
copy number changes, are reasonable candidates for disease
susceptibility variants. The association of a copy number
change in the CCL3L1 gene and susceptibility to HIV might
represent the tip of the ice berg, where polymorphic copy
number changes have a link to a phenotype (42). Well established examples of Mendelian disorders caused by genomic
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Figure 2. Overall strategy of the use of exceptional families with Mendelian information of disease trait in studies addressing genetic predisposition of common
diseases.
rearrangements include Charcot – Marie – Tooth (CMT), Di
George Syndrome, Prader –Willi and Angelman Syndromes.
The CMT locus is especially interesting, rich in low copy
number repeats, where different rearrangements result in
different phenotypes (43). The hypothesis has been put
forward that perhaps, low copy number repeats are analogous
to the changes introduced by a replication error at a nucleotide
base: both are endogenous molecular mechanisms that introduce variation into our genome (43). Thus, it is logical that
both types of variations represent potential susceptibility variations to complex phenotypes.
An interesting example of a rare translocation that has
guided to a novel, previously unknown pathway, potentially
affected in psychiatric disorders emerges from recent data of
the involvement of the DISC1 gene in the genetic background
of schizophrenia and other psychoses. Initially, the genetic
locus on 1q42 was identified as a potential site for mental
illness susceptibility gene(s) based on a translocation (1;11)
(q42.1; q14.3) in a large Scottish family with multiple
family members affected with major mental illness. The observation of the linkage in the Finnish schizophrenia pedigrees on
1q42 targeted the research effort to the 1q42 locus (44,45) and
linkage for 1q42 to schizophrenia but also to other forms of
psychosis was subsequently reported from multiple populations making this locus one of the most encouraging
among the multiple loci reported for psychosis. When the
gene interrupted by the translocation at the 1q42 locus was
identified, it was found that in fact two genes on opposite
strands were directly disrupted by the translocation, and got
named as disrupted in schizophrenia 1 and 2 (DISC1 and
DISC2) (46). Dissection of the biological role of these genes
has greatly strengthened their positions as candidates for a
role in the etiology of psychiatric disorders. Protein-protein
interaction studies show that DISC1 acts as a ‘scaffold’ for
proteins known to be involved in numerous neuronal functions, impacting on neurite outgrowth, neuronal migration,
cytoskeletal modulation and signal transduction (47). The
DISC2 gene is not known to encode a protein but rather
through its RNA acts as a regulator of DISC1. Such examples
demonstrate what a wonderful resource for studies of complex
traits exists in rare genomic rearrangements that can currently
be identified with dramatically increased resolution using
array-based technologies (48).
CONCLUSION
Have studies on Mendelian, nearly monogenic diseases educated us about common, more complex traits? During past
decades, the scientific community has actually quite successfully used special families and other study samples with
restricted number of ancestral chromosomes (like those from
isolated populations) for genetic studies of inherited disease
phenotypes and characterized the underlying molecular
Human Molecular Genetics, 2006, Vol. 15, Review Issue 1
defect. Accurate cataloging of clinical details and following
genetic investigations of over 7000 well defined Mendelian
disorders have facilitated the characterization of the molecular
defect for over 1700 among them (http://www.ncbi.nlm.nih.
gov/Omim). Our success to define the molecular background
of Mendelian diseases has in many ways formed the basis
for most promising initial findings in complex disease entities
(13,49). Most so far proposed complex disease genes have
been identified based on the ‘Mendelian’ approach, simply
because it has been a most powerful strategy. The successes
in the identification of genes for both monogenic diseases
and rare familial forms of common diseases have opened
new avenues for common disease studies via exposing new
pathways or molecules proteins previously unsuspected to
be associated with a given trait (Fig. 2). Although this
‘Mendelian’ strategy will probably not identify all the DNA
variants affecting complex disease phenotypes, it still might
be the only surviving or at least the most efficient strategy
to expose the critical pathways defective in human disease
processes. New hypothesis can be created and novel
pathway components monitored in complex diseases on the
basis of the findings in Mendelian diseases. We are far from
exhausting this wonderful resource of exceptional families
and subpopulations on the global scale. Hopefully the
examples provided in this review would further stimulate
investigators to intensify the efforts to efficiently use the
worldwide resources of rare families, they are most relevant
for improved characterization of molecular processes resulting
in common diseases.
ACKNOWLEDGEMENTS
The study was in part supported by grants from the Academy
of Finland (213506), the GenomEUtwin (QLG2-CT-200201254) and Eurohead (LSHM-CT-2004-504837) projects,
the Sigrid Juselius Foundation, The Nordic Center of
Excellence for Disease Genetics and the National Institutes
of Health, USA [RO1NS37675 (A.P.), RO1NS43559 (L.P.),
RO1HL70150-01A1 (L.P.)].
Conflict of Interest statement. None declared.
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