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c h 662
Peer reviewed article

Genetics of narcolepsy
and other major sleep disorders
Stéphanie Maret, Mehdi Tafti
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

Summary
One third of the population is affected by a vances in the genetics of narcolepsy and the role of
sleep disorder with a major social, medical, and the hypocretin/orexin system, the possibility that
economic impact. Although very little is known other gene defects may contribute to the patho-
about the genetics of normal sleep, familial and physiology of major sleep disorders is worth in-
twin studies indicate an important influence of ge- depth investigation.
netic factors. Most sleep disorders run in families
and in several of them the contribution of genetic Key words: HLA; narcolepsy; apnea; sleepwalking;
factors is increasingly recognised. With recent ad- Kleine-Levin syndrome

Introduction
In the past few years study of the molecular and have dramatic health, social, and economic im-
basis of sleep-wakefulness regulation has become pacts. Their treatments remain largely sympto-
a major and productive new field in neuroscience. matic owing to our ignorance of their molecular
Starting in 1997 with our first report of mapping pathophysiology. However familial and twin stud-
genes for the amount and distribution of normal ies indicate the presence of important genetic fac-
sleep in mice and more recently with the discov- tors in a large number of sleep disorders. Any dys-
ery of hypocretin/orexin deficiency by Emmanuel function in the expression and the regulation of
Mignot’s laboratory in canine and human nar- sleep results in a complex sleep disorder that needs
colepsy, the genetics of sleep and sleep disorders is integrated clinical and laboratory investigations.
emerging as one of the most promising avenues in The genetic dissection of well-characterised sleep
our understanding of the basic mechanisms regu- disorders might improve treatments and also pro-
lating the complex behaviour sleep. Sleep disor- vide fundamental insights into the underlying neu-
ders are highly prevalent in the general population robiological bases of normal sleep and wakefulness.

Can a single gene defect cause a sleep disorder?

In 1986, Lugaresi and colleagues described a 178 results in the substitution of asparagine for
53 year-old man who suffered from progressive aspartate. Familial Creutzfeld-Jacob disease (CJD)
insomnia, dysautonomia, dysarthria, tremor, later is also associated with codon 178 mutation and
myoclonus and coma identifying the first sleep dis- spongiform neurodegeneration leading to demen-
order for which a gene mutation has been identi- tia. However the FFI patients have a methionine
fied: fatal familial insomnia (FFI) [1]. The major at codon 129 whereas CJD patients have a valine
features of FFI include a progressive reduction of at this position. Furthermore homozygosity at
total sleep time, early disappearance of sleep spin- codon 129 was associated with a more rapid dis-
dles, loss of slow wave sleep, and disintegration of ease course in both FFI and CJD patients and
sleep cyclic organisation. This neurodegenerative lower age of onset in CJD patients [2].
disorder is caused by a point mutation at codon Familial advanced sleep phase syndrome
178 of the Prion protein gene (PrP) and is respon- (FASPS) is a highly penetrant autosomal dominant
sible for a degeneration of specific thalamic nuclei. abnormality of human circadian behaviour, which
FFI affects both sexes equally in an autosomal produces a striking 4 hour advance of the daily
No financial dominant manner with high penetrance and is sleep-wakefulness rhythm. hPer2, a human ho-
support declared.
uniformly fatal. The identified mutation at codon molog of the Drosophila period gene was found to
 S W I S S M E D W K LY 2 0 0 5 ; 1 3 5 : 6 6 2 – 6 6 5 · w w w . s m w . c h 663

be mutated in affected members of one family with acid arginine for histidine at position 192 (R192H)
FASPS [3]. A mutation at position 2106 (A to G) in the gene coding GABA-A beta3 subunit and
of the casein kinase I epsilon (CKIe) binding re- alters the GABA-A receptor function in vitro [5].
gion of hPer2 gene on chromosome 2 leads to a The Beta-3 subunit is presumed to be implicated
substitution of a serine at amino acid 662 with a in sleep processes by the observation that beta3
glycine (S662G) and is therefore responsible for Knockout mice do not respond to the hypnotic
FASPS. However not all the families tested, and action of oleamide [6].
not all the members of the same family are linked Although highly rare, the three above exam-
with the hPer2 locus, suggesting a genetic hetero- ples together with a single narcolepsy case (see
geneity in FASPS. A recent study identified a below), clearly indicate that single gene defects can
missense mutation (T44A) in the human CKIdelta produce substantial alterations of sleep. However
gene in a family affected by FASPS. An A to G mu- sleep is a highly complex behaviour and as such is
tation was identified, which causes a threonine- regulated by the action of many genes, environ-
to-alanine alteration at amino acid 44 in the mature ment, and gene-environment interactions. Sleep is
protein [4]. therefore a complex trait where the contribution
Molecular studies of primary insomnias are of susceptibility or protective genetic factors will
very rare but a recent study reported a missense lead to either its normal variation in the popula-
mutation in a single patient with chronic insom- tion (eg, short vs long sleepers), or to complex
nia. This mutation is a substitution of the amino sleep disorders such as narcolepsy.

Narcolepsy and genetic susceptibility to sleep disorders

Among highly prevalent sleep disorders the netic heterogeneity, phenocopy, incomplete pene-
contribution of genetic factors to parasomnias, trance, and variable expressivity may complicate
enuresis, restless legs syndrome and periodic limb the discovery of the underlying genes. Only a few
movements in sleep, and sleep apnoea syndromes sleep disorders have so far been investigated at the
is now well demonstrated [see table 1]. Most of molecular genetic level but narcolepsy represents
the available evidence comes from twin studies a unique model of a complex sleep disorder for
where the relative contribution of genetic and en- which substantial genetic evidence is available. As
vironmental factors can be assessed. In the case of discussed below even if the recently discovered
simple disorders the concordance rate in mono- hypocretin-orexin deficiency is the best biological
zygotic twins (probability of same phenotype in marker of narcolepsy, the condition remains com-
co-twins) is usually high (close to 100%), while in plex in terms of its molecular basis.
complex disorders the concordance rate is usually Narcolepsy-cataplexy is a rare but a highly dis-
low (usually less than 50%). Therefore the concor- abling disorder of vigilance affecting 0.02–0.06%
dance rate in monozygotic twins reflects a direct of the general population. The onset of the disease
measure of respective contribution of genetic is generally between 15 and 30 years old and af-
and environmental factors. In some disorders the fects both sexes equally. Excessive daytime sleepi-
possibility of a single autosomal dominant gene ness leads characteristically to irresistible and daily
effect cannot be ruled out. However even in these repeated sleep periods while cataplexy is defined
disorders (eg, enuresis, restless legs syndrome), ge- as a “sudden bilateral loss of postural muscle tone

Table 1. Disorder family history twin studies linkage evidence candidate gene mode of transmission*
Genetic contribution Sleepwalking Familial in up to 80%, 5 fold increased none HLA-DQB1*05 autosomal dominant
to sleep disorders. higher risk in concordance in MZ HLA-DQB1*04 or unknown [19–20]
1st degree relatives
Obstructive Higher risk in Higher concordance QTL on 1p, 2p, ApoE4 autosomal dominant
Sleep Apnoea 1st degree relatives in MZ for snoring 12p, 19p, 4q, 8q or unknown [21–22]
(in African-Americans)
Enuresis Over 75% in Higher concordance 8q, 13q, 12q, 22q11 None Autosomal dominant
1st degree relatives in MZ [23]
RLS, PLMS 63–92% familial history Higher concordance 12q MAO-A Autosomal dominant
in MZ or recessive [24–25]
Kleine-Levin Very few Familial cases No studies None HLA-DQB1*0201 Unknown [26]
Syndrome
RBD No studies Higher concordance None HLA-DQB1*05 Unknown [27]
in MZ HLA-DQB1*06
DSPS 50% have relatives No studies None HLA-DR1 Autosomal dominant
with similar symptoms hPER3, AA-NAT or unknown [28–29]
* based on pattern of transmission in families where the effect of a single gene is evident. MZ: monozygotic twins; QTL:
quantitative trait loci; RLS: restless legs syndrome; PLMS: periodic limb movements in sleep; RBD: REM sleep behaviour disorder;
DSPS: delayed sleep phase syndrome; AA-NAT: arylalkylamine N-acetyltransferase
Genetics of narcolepsy and other major sleep disorders 664

in association with intense emotion” but the pa- the Dog Leukocyte Antigen. After intensive work
tient remains totally conscious. over the past 15 years on the genetics of canine
Up to 10% of narcolepsies are familial. Dif- narcolepsy at Stanford University, Mignot’s group
ferent studies have shown that besides the typical identified, through linkage analysis and positional
phenotype, attenuated forms of the condition cloning, mutations in the hypocretin-2 receptor
characterised by isolated excessive daytime sleepi- as the cause of narcolepsy [14]. Simultaneously,
ness do exist at much higher rates; 10–40% of first Yanagisawa’s group discovered in the mouse a phe-
degree relatives of narcoleptics may be affected. notype similar to canine and human narcolepsy
However twins studies report 25–31% of concor- after a targeted deletion of the prepro-hypocretin
dance suggesting a major contribution of environ- gene [15]. The human prepro-hypocretin gene lo-
mental factors. cated on chromosome 17q21 consists of two exons
Narcolepsy has one of the tightest associations and one intron. Hypocretin-1 and -2 are hypothal-
with a specific HLA allele. A first study reported amic neuropeptides and act through hypocretin
100% association between narcolepsy and the receptor-1 and -2 first identified to be implicated
HLA-DR2/DQw1 haplotype in Japanese patients in feeding behaviour. Recently it was discovered
[7], a finding quickly confirmed in Caucasians. Four that narcolepsy patients have low or undetectable
alleles corresponding to DRB1*1501, DRB5*0101, hypocretin-1 levels in their CSF [16] and that there
DQA1*0102, and DQB1*0602 are associated with is a dramatic reduction in the number of hypothal-
narcolepsy but DQB1*0602 constitute the major amic hypocretin-containing neurons in a small
HLA susceptibility allele across all ethnic groups. number of post-mortem narcolepsy cases [17].
The more striking fact is that 88–98% of patients Also transgenic mice carrying the promoter of the
affected by narcolepsy with clear cataplexy are HLA human prepro-hypocretin gene ligated to trun-
DQB1*0602 positive. This allele strongly increases cated human ataxin-3, a gene that induces apop-
the susceptibility for cataplexy although 41% of tosis of hypocretin containing neurons, present
patients without cataplexy are carriers. DRB1 and symptoms similar to human narcolepsy [18]. A sin-
DQB1 genes have been sequenced in narcolepsy gle presumably pathogenic mutation has been
patients but no mutation was identified suggesting found in an atypical narcolepsy child [17] but de-
that they strongly confer susceptibility to deve- spite the compelling evidence for a causal implica-
lopment of the disease without their function tion of the hypocretin system none of the three
being defective. Therefore non-HLA genes such genes involved is found mutated in narcolepsy pa-
as monoamine oxidase-A (MAO-A) [8], tumour tients and there is no evidence for any association
necrosis factor alpha (TNF-A) [9], TNFR2 (in between polymorphisms identified in genes en-
Japanese) [10], and catechol-O-metyltransferase coding the prepro-hypocretin and its receptors
(COMT) [11] may in addition or independent of and human narcolepsy. Since 90% of human cases
HLA also be involved in susceptibility to narcolepsy. of narcolepsy are sporadic and monozygotic twins
Familial forms of narcolepsy with several members show only partial concordance (25–31%), the de-
of a family affected are rare. A first study, however, velopment of this disease could involve environ-
reported a suggestive linkage to chromosome 4p13- mental factors interacting with specific genetic
q21 [12] in 8 small Japanese families. In a second susceptibility factors. Therefore together with the
study, from our laboratory, significant evidence for tight association with the HLA antigens, the most
linkage with a locus in a 5 Mb region of chromo- likely cause of hypocretin deficiency in narcolepsy
some 21q could be established [13]. might be an autoimmune process resulting in
Narcolepsy is also found in Dobermans and acute or progressive degeneration of hypocretin-
Labradors and is clinically and electro-physiolog- containing neurons in the hypothalamus. The
ically similar to the human disease. Canine nar- environmental factor(s) might trigger narcolepsy
colepsy is transmitted as a single autosomal reces- by inducing an autoimmune reaction that targets
sive trait with full penetrance and is not linked to hypocretin neurons.

Conclusions

The list of sleep disorders with a genetic con- finding suggests a fundamental relationship be-
tribution is rapidly expending and those reviewed tween sleep and the immune system, which re-
here constitute significant examples only. Other mains to be discovered. The immune system may
common sleep disorders such as insomnia and modulate brain activity and sleep or at least these
nightmares and rare disorders such as idiopathic two systems seem to influence each other and in-
hypersomnia might well be controlled by genetic teract intimately. Because sleep and sleep disorders
factors. The most striking finding remains the are complex both in their manifestations and reg-
HLA association found in narcolepsy, sleepwalk- ulation, several approaches are needed to further
ing, Kleine-Levin syndrome, and REM sleep be- our understanding of their molecular basis. Stud-
haviour disorder. Although not a single common ies in animal models like drosophila, zebrafish, and
feature can be proposed in these disorders, this mice could be complemented with genetic linkage
 S W I S S M E D W K LY 2 0 0 5 ; 1 3 5 : 6 6 2 – 6 6 5 · w w w . s m w . c h 665

studies, association studies, and genome-wide

Correspondence:
association studies in humans. This could lead to
Prof. M. Tafti
a better understanding of sleep mechanisms and
Faculty of Biology and Medicine
ultimately help the development of appropriate
Center for Integrative Genomics
treatments for sleep disorders.
University of Lausanne
CH-1015 Lausanne
Acknowledgements
The authors are supported by the Canton of Vaud and
[email protected]
the Swiss National Science Foundation.

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