Linkage mapping of a new syndromic form of X-linked mental retardation, MRXS7, associated with obesity

Abstract

A new syndromic form of X-linked mental retardation associated to obesity, MRXS7, has been localised to Xp11.3-Xq23 in a large Pakistani family. The ten affected males show clinical manifestations of mental retardation, obesity and hypogonadism. The family was genotyped by a set of microsatellite markers spaced at approximately 10 cM intervals on the X chromosome. Linkage to five adjacent microsatellite markers, mapping in the pericentromeric area, was established and a maximum two-point lod score of 3.86 was reached at zero recombination with marker DXS1106. Reduced recombination events around the centromere prevented precise mapping of the gene.

Full text

SHORT REPORT
Linkage mapping of a new syndromic form of
X-linked mental retardation, MRXS7, associated
with obesity
Wasim Ahmad
1
, Maurizio De Fusco
1
, Muhammad Faiyaz ul Haque
2
, Paolo Aridon
1
,
Tiziana Sarno
1
, Muhammad Sohail
3
, Sayed ul Haque
4
, Mahmud Ahmad
4
,
Andrea Ballabio
1,5
, Brunella Franco
1
and Giorgio Casari
1
1
Telethon Institute of Genetics and Medicine, Milan, Italy
2
Department of Neurology, Cell and Molecular Biology, Northwestern University Medical School, Chicago, IL, USA
3
Department of Biochemistry, University of Oxford, UK
4
Department of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
5
Universita’ Vita Salute, Milan, Italy
A new syndromic form of X-linked mental retardation associated to obesity, MRXS7, has been
localised to Xp11.3–Xq23 in a large Pakistani family. The ten affected males show clinical
manifestations of mental retardation, obesity and hypogonadism. The family was genotyped by
a set of microsatellite markers spaced at approximately 10 cM intervals on the X chromosome.
Linkage to five adjacent microsatellite markers, mapping in the pericentromeric area, was
established and a maximum two-point lod score of 3.86 was reached at zero recombination
with marker DXS1106. Reduced recombination events around the centromere prevented
precise mapping of the gene.
Keywords: X-linked mental retardation; obesity; linkage mapping
X-linked mental retardation (XLMR) is the most
common cause of mental retardation in males. XLMR
can be divided into syndromic and non-specific forms.
1
Both non-specific and non-syndromic forms of
X-linked mental retardation (MRX) are genetically
heterogeneous. Affected males in families segregating
MRX have no consistent clinical or somatic manifesta-
tions, apart from their mental retardation, to dis-
tinguish them from unaffected family members. Several
XLMR loci have already been mapped by linkage
analysis. Lubs and colleagues
2
listed 147 XLMR condi-
tions. Among these, 105 consisted of syndromic forms
of MRXS and 42 were described as non-specific forms
of mental retardation. However, only 18 genes respon-
sible for MRXS and five genes for MRX (FRAXE,
3
GDI1,
4
PAK3,
5
oligophrenin-1,
6
and RSK2
7
have been
cloned so far.
In the present study we describe a family with mild to
moderate forms of mental retardation, which is asso-
ciated with clinical manifestations such as obesity,
hypogonadism, micropenis, tapering fingers, hairless
body, eyesight and dental anomalies, speech disabilities,
and diminished body strength. Linkage analysis local-
ises the gene responsible for this form of mental
retardation to Xp11.3–Xq23.
Correspondence: Dr Giorgio Casari, Telethon Institute of
Genetics and Medicine, San Raffaele Biomedical Science
Park, Via Olgettina 58, 20132 Milan, Italy. Tel: 39 02 21560201;
Fax: 39 02 21560220; E-mail: casari@tigem.it
Received 21 October 1998; revised 21 May 1999; accepted 9
June 1999
European Journal of Human Genetics (1999) 7, 828–832
© 1999 Stockton Press All rights reserved 1018–4813/99 $15.00
http://www.stockton-press.co.uk/ejhg

Materials and Methods
Clinical Description
The pedigree is represented in Figure 1. Female members of
the family, including obligate carriers, show no signs of mental
deficiency. Patient III-2 is 50 years old, moderately mentally
retarded, unable to read and write, and his speech is difficult
to understand. His height is 145 cm and weight 120 kg, with
normal facial appearance. Hair is present on the face but
absent on the rest of the body, including the pubic area. He
has a micropenis and small testes. Feet are normal but with
pes planus, fingers are slightly tapered, and body strength is
highly diminished. Patient IV-4 is a 20-year-old mildly
affected male. He has never attended any type of school and
is unable to read or write, although he can communicate with
other people when required. His height is 150 cm and weight
83 kg. He has normal body and facial hair, although scanty in
the pubic area; penis and testes are small, and feet and fingers
are normal.
Patient IV-6, 18 years old, weight 87 and height 160 cm, is
moderately affected and unable to read, write, or perform
simple calculations; phallus is very small and testes are not
descended; hair is present only on the face; feet are small,
fingers tapered, and body strength is remarkably below
average. The clinical history of patients IV-9 and IV-10 are not
available. They were obese and died at the ages of 8 and 10,
respectively, due to accidents. Patient IV-11, 25 years old, is
moderately affected; his height is 165 cm and weight 85 kg.
Facial hair is normal but absent on the rest of the body,
including the pubic area. Like other affected members of the
family, he presents severe micropenis; his speech is extremely
difficult to understand; fingers are slightly tapered and body
strength is diminished.
Patient IV-12, 24 years old, is mildly affected. He can follow
commands and perform simple calculations. His height is
177 cm and weight 97 kg. Teeth are malpositioned and
malformed; testes and phallus are small; foot size is normal
but with pes planus; fingers are tapered; the speech is clear
except for occasional slurring. Patient IV-17, 16 years old, is
moderately mentally retarded with extreme speech disability;
height 152 cm and weight 82 kg; tapered fingers, pes planus,
and decreased muscular strength are present. Both maxillary
and mandibular incisors are malformed and malpositioned.
Patient IV-19, 13 years old, is severely mentally retarded and
almost completely blind in both eyes; height is 137 cm and
weight 75 kg. Besides common traits such as micropenis, non-
descended testes, and absence of body hair, he presents the
most severe dental anomalies of all patients, with mandibular
incisors malpositioned and malformed and eight axillary
incisors arranged in two rows.
The endocrinological evaluation (FSH, LH, testosterone
concentration) of affected members III-2, IV-4, and IV-6
shows normal values. The IQ test performed on all affected
members ranges between 40 and 50.
Genotype and Linkage Analysis
A set of fluorescence labelled markers (DXS1060, DXS987,
DXS1226, DXS1202, DXS1214, DXS1068, DXS993,
DXS1055, DXS991, DXS986, DXS990, DXS1106, DXS1001,
DXS1047, and DXS1227) was used for primary screening.
Figure 1 MRXS7 pedigree. Haplotypes for selected markers in Xp11.3–q23 are shown. Markers DXS8083, DXS1055, DXS991,
DXS986, DXS990, DXS1106, DXS8063, and DXS8112 are ordered pter (up) to qter (down). Arrows indicates the recombination
events
Syndromic mental retardation and obesity on Xp12–q23
W Ahmad et al
829

Further refinement of the localisation was carried out by
locally increasing the marker map density. Two-point linkage
analysis between each marker and the disease locus was
performed using the computer program LINKAGE 5.1,
8
assuming X-linked recessive inheritance. The frequency of the
disease allele was chosen arbitrarily as 0.00001. Genetic
distances of the marker loci were used as described by Dib et
al.
9
Results
Fourteen family members were enrolled in a genetic
linkage study, including seven affected and seven
unaffected subjects. Twenty-two highly polymorphic
markers (the fluorescence labelled set of markers,
DXS8083, DXS8063, DXS8112, DXS1210, DXS1059,
DXS8088, and DXS8055) spanning from Xpter to
Xqter were genotyped. The two-point lod score table
between the MRXS7 disease locus and markers is
presented in Table 1. Evidence of linkage was observed
with six markers (DXS1055, DXS991, DXS986,
DXS990, DXS1106, and DXS8063) covering a 38 cM
area with regional localisation at Xp11.3–Xq23. How-
ever, the chromosomal area spanning the two closest
recombinant markers, DXS8083 and DXS8112, is
42 cM.
The maximum lod score value 3.86 was reached with
DXS1106 at zero recombination. Multipoint linkage
analysis was performed with markers DXS8083,
DXS1055, DXS986, DXS1106, DXS8063 and
DXS8112, resulting in a broad peak, which includes all
the significant markers and reaches a maximum multi-
point lod score of 4.20 (data not shown). Haplotype
analysis presented in Figure 1 for markers DXS8083,
DXS1055, DXS991, DXS986, DXS990, DXS1106,
DXS8063, and DXS8112 showed recombination events
defining the boundaries of the critical region. Unaf-
fected male IV-3 recombines with marker DXS8083,
2.7 cM distant from DXS1055, defining the p arm
boundary; affected member IV-6 shows with marker
DXS8112 and therefore places the Xq boundary in the
2.9 cM between DXS8063 and DXS8112.
Discussion
Mental retardation associated with manifestation of
obesity, hypogonadism, microphallus, tapering fingers,
hairless body, speech disability, eyesight and dental
anomalies, and decreased body strength in a family of
10 affected males supports the hypothesis of a new
X-linked recessive mental retardation syndrome. None
Table 1 Two-point lod scores for MRXS7 family
θ
0.00 0.01 0.05 0.10 0.20 0.30 0.40
marker
DXS1060 –inf –1.63 –0.93 –0.63 –0.33 –0.16 –0.06
DXS987 –inf –4.08 –2.05 –1.23 –0.50 –0.17 –0.03
DXS1226 –inf –4.29 –1.63 –0.60 0.19 0.40 0.32
DXS1202 –inf –5.99 –2.63 –1.30 –0.21 0.18 0.22
DXS1214 –inf –2.37 –0.45 0.22 0.61 0.59 0.35
DXS1068 –inf –2.60 –0.67 0.01 0.45 0.47 0.29
DXS993 –inf –2.31 –0.39 0.27 0.65 0.61 0.36
DXS8083 –inf 1.62 2.10 2.12 1.82 1.32 0.70
DXS1055 3.67 3.61 3.37 3.06 2.39 1.66 0.85
DXS991 3.74 3.68 3.43 3.11 2.43 1.69 0.86
DXS986 3.67 3.62 3.38 3.08 2.42 1.69 0.87
DXS990 3.18 3.13 2.91 2.62 2.02 1.38 0.69
DXS1106 3.86 3.80 3.54 3.21 2.50 1.74 0.89
DXS8063 3.19 3.13 2.91 2.63 2.02 1.34 0.58
DXS8112 –inf 1.14 1.64 1.67 1.41 0.97 0.41
DXS1210 0.17 0.16 0.14 0.11 0.07 0.03 0.01
DXS1059 0.17 0.16 0.14 0.11 0.07 0.03 0.01
DXS8088 –inf 1.14 1.64 1.67 1.41 0.97 0.41
DXS8055 –inf –2.31 –0.39 0.26 0.65 0.61 0.36
DXS1001 0.22 0.21 0.19 0.15 0.09 0.03 0.00
DXS1047 –inf –7.70 –3.68 –2.10 –0.77 –0.22 –0.01
DXS1227 0.18 0.17 0.15 0.12 0.07 0.02 –0.01
Syndromic mental retardation and obesity on Xp12–q23
W Ahmad et al
830

of the observed manifestations are detected in any
normal members of the family. Lubs and co-workers
2
provided a comprehensive list of all forms of X-linked
mental retardation, altogether 147 entries, consisting of
105 syndromic and 42 non-specific forms. Some of the
clinical anomalies observed in patients with various
disorders overlap with the syndrome described in this
study. The MEHMO syndrome (mental retardation,
epilepsy, hypogonadism, microcephaly, and obesity
10
)
locus maps on Xp21–22, external to the MRXS7 critical
region. Wilson et al
11
describe 14 affected males through
three successive generations in a large family with
X-linked mental retardation, characterised by obesity,
gynecomastia, speech difficulties, emotional lability,
tapering fingers, small feet, and hypogonadism (Wilson-
Turner syndrome).
However, the major clinical manifestation described
in the affected subjects, gynecomastia, is a finding
absent in our MRXS7 patients. The candidate region
for the MRXS7 gene (Xp11.3–Xq23) overlaps with that
of the Wilson-Turner syndrome, Xp21.1–Xq22.
11,12
Although clinical manifestation of gynecomastia is
absent in our patients, the possibility that a single gene
is involved in both MRXS7 and Wilson-Turner syn-
drome cannot be excluded. Two more XLMR syn-
dromes associated with obesity, hypogonadism, and
short stature exhibit some clinical overlap with patterns
of MRXS7 patients. Vasquez et al
13
identified a family
with five affected males through four generations with
mental retardation, obesity, hypogonadism, and gyne-
comastia. The Borjeson-Forssman-Lehmann syndrome
is characterised by mental retardation, unusually coarse
face with large ears, obesity and epilepsy, and maps in
Xp27.
14
The MRXS7 critical region has been described as the
most gene-dense region after the MHC class III cluster
identified on chromosome 6.
15
Several disease genes
have been mapped to this region. They include the
androgen receptor gene,
16
the XH2 gene, responsible
for ATRX syndrome, an X-linked disorder comprising
severe psychomotor retardation, genital abnormalities,
and alpha-thalassaemia,
17
three genes responsible for
eye diseases,
18–20
Wiskott-Aldrich syndrome,
21
one form
of synovial sarcoma,
22
X-linked nephrolithiasis,
23
and
zinc finger genes (ZXDA
24
and four Kruppel type
25
).
These zinc finger genes could be considered candidates
for the syndrome described in this paper, and possibly
the Wilson syndrome, further supported by earlier
findings, showing that disruption of zinc finger genes
was involved in human development disorders such as
Greig-cephalopolysyndactyly syndrome
26
and Wilms
tumour.
27
Acknowledgements
We gratefully acknowledge the family members. We thank
Drs Mohammad Ayub and Mohammad Andaleeb for helping
with clinical diagnosis. This work was supported by the Italian
Telethon Foundation to TIGEM and WA (postdoctoral
fellowship 205/bs). MA was supported by the Pakistan
Science Foundation (PSF).
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