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A Family With X-linked Dystonia-Deafness Syndrome With a Novel Mutation of the DDP Gene
Hiroshi Ujike, MD, PhD;
Yasuyuki Tanabe, MD, PhD;
Yasushi Takehisa, MD;
Toshiyuki Hayabara, MD, PhD;
Shigetoshi Kuroda, MD, PhD
Arch Neurol. 2001;58:1004-1007.
ABSTRACT
Background X-linked dystonia-deafness syndrome (DDS) is characterized by early-onset
deafness followed by progressive dystonia in adulthood. Only 4 families with
the syndrome have been reported, and all were white.
Objective To describe the first nonwhite family with X-linked DDS, involving 5
affected males in 4 generations.
Results Clinical features of the family members, who were Japanese, were mostly
consistent with reports of DDS in whites except for a lack of visual disturbances.
Whereas microdeletions in the deafness-dystonia peptide (DDP) gene were found in 2 white DDS families, our patients showed a
novel mutation (arg80ter) in exon 2 of the DDP gene.
Conclusion The existence of a DDS family of Japanese origin with a new kind of
mutation in the DDP gene provides additional evidence
that the DDP gene is a causative gene for X-linked
DDS.
INTRODUCTION
X-LINKED dystonia-deafness syndrome (DDS) was originally reported as
X-linked deafness in a Norwegian family by Mohr and Mageroy1
in 1960, and designated as DFN-1. The family was later studied by Tranebjaerg
et al,2 who found that the patients had not
only deafness but also several other symptoms, including progressive dystonia.
They named the syndrome the Mohr-Tranebjaerg syndrome. X-linked DDS is characterized
by postlingual progressive sensorineural deafness as the initial symptom occurring
in early childhood followed by progressive dystonia, mental deterioration,
cortical blindness, spasticity, and psychiatric manifestations. To date, 4
families with X-linked DDS have been reported, 2, 3, 4, 5
and were all white. We report the first nonwhite family (Japanese) with X-linked
DDS, affecting 5 males from 4 generations.
REPORT OF CASES
PROBAND
Proband III-6 (Figure 1),
a 39-year-old Japanese man, was born by normal delivery and was of average
birth weight, but found to be deaf at age 6 months. He had shown no developmental
delay or any other neurological symptoms except for deafness. He graduated
from a high school for the deaf and mute, worked in a timber plant, and lived
alone. He obtained a driver's license and drove a car. He first noticed stiffness
in the upper limbs and difficulty holding a cup and using chopsticks at the
age of 30 years, and this gradually progressed. At the age of 34 he was examined
by neurologists, who found sensorineural deafness, dystonia in the upper limbs,
brisk deep tendon reflexes in all 4 limbs, and clonus in the lower limbs that
decreased 5 to 10 seconds after induction. There were no visual or sensory
disturbances, ataxia, autonomic symptoms, or pathological reflexes. Mental
deterioration was found, but it was mild. Electroencephalography showed excess
theta waves of 6 to 7 Hz with a diffuse distribution. Brain magnetic resonance
imaging revealed moderate cortical atrophy, especially in the frontal cortex,
and moderately dilated third and fourth ventricles. An electroretinogram was
normal. Electromyography showed normal motor and sensory nerve conduction
velocity. At the age of 35, the dystonia had extended to the lower limbs and
blepharospasm was also evident. He began to need a cane for walking and standing.
The dystonia did not respond to levodopa, carbamazepine, or trihexyphenidyl
hydrochloride therapy. In recent years, the patient showed personality changes,
becoming unstable and of uneven temperament.
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Figure 1. Family pedigree. Dagger indicates
that individual I-1 was dead when we examined the propositus' family history.
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CASE 2
Individual III-5 (Figure 1),
the 41-year-old brother of the propositus, was born by normal delivery and
found to be deaf at 4 years of age. He did well in regular primary and junior
high school and graduated. At the age of 16, he noticed mild dystonia in his
neck, trunk, and upper limbs. This gradually progressed, and by age 27, it
had extended to his lower limbs, resulting in clumsiness while walking. By
age 29, he frequently fell and needed assistance for daily activities such
as bathing and eating. By age 31, he needed a cane for walking, and at 33,
blepharospasm was evident. He showed mild mental deterioration but no personality
changes or psychiatric symptoms. There was no visual disturbance.
CASE 3
Individual I-1 (Figure 1),
the grandfather of the propositus, died when he was 89 years old. Exact information
was not available, but it appeared that he was deaf and had slight dystonia
in the lower limbs.
CASE 4
Individual III-7 (Figure 1),
a 35-year-old maternal male cousin, was born by normal delivery and was found
to be deaf at 3 to 4 years of age. The deafness was not severe, because he
had no difficulty hearing when wearing a hearing aid. He showed mild dystonia
in all 4 limbs. His use of chopsticks and writing became clumsy when under
stress, and his walking was slow with a tendency to stumble, although he did
not need any assistance for daily activities. He graduated from high school
and was a successful farmer. There was no mental deterioration.
CASE 5
Individual IV-4 (Figure 1),
a 15-year-old maternal nephew, was born by normal delivery. He was found to
be deaf in a lower grade of primary school at 8 or 9 years of age. His deafness
was compensated for fully by a hearing aid, and he showed no dystonia or mental
retardation.
METHODS
Genomic DNA was extracted from peripheral leukocytes by the phenol-chloroform
method. Two exons of DDP were amplified by polymerase
chain reaction using unique primer sets according to the method of Jin et
al3 (exon 1: 5'-GCGGAGTTCGTCTCTGCAAGC-3',
5'-GTAGGTACAGTGTTTAGGTC-3', exon 2: 5'-GTTCACTGGCTAGATTCC-3',
5'-CTAAGCAACAAAAAGGGAC-3') in a 15-µL reaction volume consisting
of 300 ng of genomic DNA; 1 X polymerase chain reaction buffer, deoxynucleotide
triphosphates, 200 µmol/L; forward and reverse primers, 0.4 µmol/L;
and 1.5 U of ExTaq (Takara Shuzo Co Ltd, Kyoto, Japan). The polymerase chain
reaction products were separated on 3% agarose gel and purified, and were
sequenced directly.
RESULTS
Sequence analysis of case 1 revealed that CGA codon 80 of exon 2 was
replaced by TGA, resulting in substitution of arginine by a stop codon (Figure 2). The mother of case 1 was shown
to be a heterozygote of the normal and nonsense mutated alleles. This mutation
breaks a cognition site of the restriction enzyme TaqI.
Restriction fragment length polymorphism analysis using TaqI revealed that the affected males (cases 1, 2, and 4) had a single
band of 859 base pairs that was not cleaved by TaqI
(Figure 3). However, the father
of case 1 (II-4), who had no symptoms of DDS, showed 2 bands of 676 bp and
189 bp that were cleaved by TaqI. The mother of case
1 (II-3) and the mother of case 4 (II-5) showed 3 bands, a single uncleaved
band and 2 cleaved bands, that indicated that they were carriers. These obligate
carriers did not show any symptoms of DDP. The maternal
aunt of case 1 (II-1), who had only 1 healthy grandson as a male descendant,
was also found to be a carrier. The mutation in exon 2 was screened for using TaqI in 50 healthy volunteers (25 males, 25 females) and
was found to be absent in normal subjects.
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Figure 2. Sequence analysis of the propositus
and his parents in codons 79 to 81 of exon 2 in the DDP gene.
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Figure 3. Restriction fragment length polymorphism
analysis of exon 2 of the DDP gene using TaqI restriction
enzyme. The normal male and female and the father of the propositus show 2
cleaved bands. Affected males (III-5, III-6, and III-7) show a single uncleaved
band. Carriers (II-1, II-3, and II-5) show 3 bands.
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COMMENT
The Japanese pedigree presented here, consisting of 5 affected males
in 4 generations, showed X-linked recessive inheritance. Their main symptoms
were neural deafness in early childhood and progressive dystonia in adulthood.
Mild mental deterioration and character changes were also seen, but visual
disability was absent. Visual disability, like cortical blindness, was seen
only in the original Norwegian family but not in the American families.2, 3, 4 In comparison with previously
reported X-linked DDS in 4 white families,2, 3, 4, 5
the symptoms and clinical course of these Japanese cases were comparable,
but generally milder (Table 1).
The onset of dystonia was later in the Japanese cases, appearing at around
15 to 30 years of age, as opposed to less than 10 years of age in the white
subjects in the other studies.2, 3, 4, 5
All of our patients were able to walk and stand with or without a cane, but
most of the white subjects became confined to a wheelchair between the ages
of 9 and 22 years. Regarding mental status, the present cases showed only
mild mental deterioration and few or no psychiatric problems. However, in
the previously reported cases,2, 3, 4, 5
mental deterioration was common, and personality changes, such as restlessness,
irritability, anxiety, and aggressive outbursts, were seen in at least half
of the patients. Symptoms of paranoia were also evident in these patients.
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Comparison of Symptoms and Clinical Course of X-linked Dystonia-Deafness
Syndrome in Multiple Studies*
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Tranebjaerg et al2 reported that the
Norwegian pedigree showed a significant linkage disequilibrium to Xq21.3-q22.
The Bruton gammaglobulinemia tyrosine kinase (BTK)
gene, which is involved in immunodeficiency X-linked agammaglobulinemia,6 is located in this region. Jin et al3
analyzed the X-linked agammaglobulinemia patients who had deafness and dystonia,
and found that deletion of the BTK gene extended
to the next gene in the 3' location of the BTK
gene. They designated this gene as DDP (deafness-dystonia
peptide) and cloned the transcript lying in that region. The DDP gene has 2 exons and a single intron of about 2 kb and encodes
a small peptide consisting of 97 amino acids. Jin et al found 2 kinds of microdeletion
in the coding region of the DDP gene in a Norwegian
patient and an American patient. In the Norwegian patient, a 1-bp deletion
(151delT) in exon 1 produced a consequent frame shift resulting in an incorporation
of 25 novel amino acids after glutamic acid at codon 38, followed by early
termination. In the American patient (pedigree K8190), a 10-bp deletion (183del10)
in exon 2 of the DDP gene produced a frame shift
resulting in the addition of 12 novel amino acids after the methionine residue
at codon 48, followed by early termination. In our cases, arginine at codon
80 was substituted by a stop codon. Therefore, this nonsense mutation produced
a truncated DDP gene of 79 amino acids. However,
this was longer than the normalamino acid sequence of those peptides produced
by the microdeletions (151delT and 183del10) of the DDP gene found by Jin et al3; normal sequences
of these have only 38 and 48 amino acids, respectively. It is possible that
the truncated peptide produced by the nonsense mutation with a longer normal
amino acid sequence could be related to the milder clinical symptoms and slower
progression of the disease seen in the Japanese patients with X-linked DDS.
The physiological function of the DDP gene is unknown.
Although it is expressed at the highest concentration in the fetal brain,
it is expressed ubiquitously in other tissues, such as the liver, heart, kidney,
and lung.7 Recently, DDP was shown to strongly resemble Tim8p, a zinc-binding yeast protein
that is implicated in the import of a class of transmembrane carrier proteins
from the cytoplasm to the mitochondrial inner membrane.7, 8
It was also found that DDP protein is located in the mitochondrial intermembrane
space.8 Therefore, mutated DDP may disrupt the mitochondrial import system and energy production,
inducing dystonia and deafness.
The finding that patients of a particular race with a different kind
of mutation (arg80ter) of the DDP gene had clinical
symptoms consistent with those of white patients with DDS strongly indicates
that the DDP gene must be a causative gene for X-linked
DDS.
AUTHOR INFORMATION
Accepted for publication September 14, 2000.
This study was supported in part by a grant from Zikei Psychiatric Institute
(Okayama, Japan).
From the Department of Neuropsychiatry, Okayama University Medical
School (Drs Ujike, Takehisa, and Kuroda), and the Department of Neurology,
National Sanatorium, Minami-Okayama Hospital (Drs Tanabe and Hayabara), Okayama,
Japan.
Corresponding author and reprints: Hiroshi Ujike, MD, PhD, Department
of Neuropsychiatry, Okayama University Medical School, 2-5-1 Shikata-cho,
Okayama 700-8558, Japan (e-mail: hujike{at}cc.okayama-u.ac.jp).
REFERENCES
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1. Mohr J, Mageroy K. Sex-linked deafness of a possibly new type. Acta Genet Stat Med. 1960;10:54-62.
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fractures, and mental deficiency is linked to Xq22. J Med Genet. 1995;32:257-263.
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3. Jin H, May M, Tranebjaerg L, et al. A novel X-linked gene, DDP, shows mutations
in families with deafness (DFN-1), dystonia, mental deficiency and blindness. Nat Genet. 1996;14:177-180.
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impairment: clinical course and pathological findings. Adv Neurol. 1976;14:235-243.
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6. Jin H, Kendall E, Freeman TC, et al. The human family of deafness/dystonia peptide (DDP) related mitochondrial
import proteins. Genomics. 1999;61:259-267.
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7. Vetrie D, Vorechovsky I, Sideras P, et al. The gene involved in X-linked agammaglobulinaemia is a member of the
src family of protein-tyrosine kinases. Nature. 1993;361:226-233.
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8. Koehler CM, Leuenberger D, Merchant S, et al. Human deafness dystonia syndrome is a mitochondrial disease. Proc Natl Acad Sci U S A. 1999;96:2141-2146.
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