Am. J. Hum. Genet. 76:510–516, 2005

510

Report

Identification of C7orf11 (TTDN1) Gene Mutations and Genetic
Heterogeneity in Nonphotosensitive Trichothiodystrophy
Kazuhiko Nakabayashi,1 Daniela Amann,3 Yan Ren,1 Ulpu Saarialho-Kere,4,5 Nili Avidan,3
Simone Gentles,1 Jeffrey R. MacDonald,1 Erik G. Puffenberger,6 Angela M. Christiano,7
Amalia Martinez-Mir,7 Julio C. Salas-Alanis,7 Renata Rizzo,8 Esther Vamos,9 Anja Raams,10
Clifford Les,11 Eric Seboun,12 Nicolaas G. J. Jaspers,10 Jacques S. Beckmann,3,13
Charles E. Jackson,14 and Stephen W. Scherer1,2

1Program in Genetics and Genomic Biology, The Hospital for Sick Children, and 2Department of Molecular and Medical Genetics, University
of Toronto, Toronto; 3Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel; 4Department of Dermatology,
University of Helsinki, Helsinki; 5Karolinska Institutet at Stockholm Soder Hospital, Stockholm; 6The Clinic for Special Children, Strasburg,
PA; 7Department of Dermatology, Columbia University, New York; 8Department of Pediatrics, University of Catania, Catania, Italy;
9Department of Medical Genetics, Hôpital Universitaire Erasme, Brussels; 10Department of Genetics, Medical Genetic Cluster, Erasmus
University, Rotterdam, the Netherlands; 11Henry Ford Hospital, Detroit; 12Division of Genetics and Microbiology, University Pierre et Marie
Curie, Paris; 13Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois et l’Université de Lausanne (CHUV-UNIL), Lausanne,
Switzerland; and 14Department of Medicine, Scott & White Memorial Hospital, Temple, TX

We have identified C7orf11, which localizes to the nucleus and is expressed in fetal hair follicles, as the first disease
gene for nonphotosensitive trichothiodystrophy (TTD). C7orf11 maps to chromosome 7p14, and the disease locus
has been designated “TTDN1” (TTD nonphotosensitive 1). Mutations were found in patients with Amish brittle-
hair syndrome and in other nonphotosensititive TTD cases with mental retardation and decreased fertility but not
in patients with Sabinas syndrome or Pollitt syndrome. Therefore, genetic heterogeneity in nonphotosensitive TTD
is a feature similar to that observed in photosensitive TTD, which is caused by mutations in transcription factor
II H (TFIIH) subunit genes. Comparative immunofluorescence analysis, however, suggests that C7orf11 does not
influence TFIIH directly. Given the absence of cutaneous photosensitivity in the patients with C7orf11 mutations,
together with the protein’s nuclear localization, C7orf11 may be involved in transcription but not DNA repair.

Trichothiodystrophy (TTD), or sulfur-deficient brittle
hair (Price et al. 1980), can be associated with a spectrum
of symptoms affecting organs of ectodermal and neu-
roectodermal origin (table 1). These include nail dystro-
phy, mental and growth retardation, ichthyosis, de-
creased fertility, and cutaneous photosensitivity, but not
cancer (Bergmann and Egly 2001). Approximately half
of patients with TDD display photosensitivity. These
cases are associated with defects in nucleotide excision
repair (NER) due to mutations in XPD (Botta et al.
1998), XPB (Weeda et al. 1997), or TTD-A (Giglia-Mari
et al. 2004) that cause a reduction of cellular concen-

Received November 8, 2004; accepted for publication December
16, 2004; electronically published January 11, 2005.

Address for correspondence and reprints: Dr. Stephen W. Scherer,
555 University Avenue, Toronto, ON M5G 1X8, Canada. E-mail:
steve@genet.sickkids.on.ca

� 2005 by The American Society of Human Genetics. All rights reserved.
0002-9297/2005/7603-0014$15.00

tration of transcription factor II H (TFIIH) (Botta et al.
2002). However, the causal gene or genes for nonpho-
tosensitive TTD are unknown.

Amish brittle-hair brain syndrome (ABHS [MIM
234050]) is an autosomal recessive disorder charac-
terized by short stature, intellectual impairment, sulfur-
deficient brittle hair, and decreased male fertility but
not cutaneous photosensitivity (Jackson et al. 1974;
Baden et al. 1976). Other forms of nonphotosensitive
TTD, such as Sabinas brittle-hair syndrome (MIM
211390) (Howell et al. 1981) and Pollitt syndrome
(MIM 275550) (Pollitt et al. 1968), were hypothesized
to be allelic with ABHS, because of similar clinical pres-
entations. Initially, to search for the ABHS disease locus,
we performed homozygosity mapping on a subset of af-
fected members from a consanguineous Amish kindred
(Jackson et al. 1974) and identified a 2-Mb candidate
locus on 7p14 (fig. 1A) (Seboun et al., in press). We then
analyzed seven genes (fig. 1A) (Scherer et al. 2003; The



Figure 1 Identification of C7orf11 mutations. To screen the two exons and the 5′ upstream region of the C7orf11 gene, we used three
sets of primer pairs: C7orf11-5upF/ex1R1, C7orf11ex1-F2/R3, and C7orf11ex2-F/R2 (for primer sequences, see table A1 [online only]). The
cycling conditions were initial denaturation at 94�C for 3 min followed by 35 cycles of denaturation at 94�C for 30 s, annealing at 58�C for
30 s, and extension at 72�C for 60 s. PCR products were purified using microCLEAN (Microsone) and were used as the sequencing template.
Sequencing reactions were performed using the Big Dye Terminator kit (Applied Biosystems), and an ABI-3730 DNA Sequencer (Applied
Biosystems) was used to obtain sequences. A, Physical map of the 2-Mb region on 7p14 showing homozygosity in a consanguineous Amish
kindred. B, Diagram of C7orf11, consisting of two exons spanning 2 kb. The coding and untranslated regions are shown as blackened and
unblackened boxes, respectively. The red and blue asterisks (*) indicate the position of the M144V mutation in the Amish kindred and the 2-
bp deletion in the Moroccan siblings with TTD, respectively. Black and red bars (numbered from 1 to 11) represent the size and location of
the PCR products in the deletion mapping for patient 6474. The fragments that were not amplified from patient 6474 (because of homozygous
deletion) are indicated by red bars. C, Five affected families from the Amish kindred. Gray and blackened symbols indicated affected members,
and unblackened symbols indicate unaffected members. The member of family B represented by the blackened symbol is the proband, who
had a more severe phenotype, presumably due to a de novo chromosomal abnormality (46,XY,14q�) (Jackson et al. 1974). The genotype at
the M144V mutation site (A, wild-type; G, mutated) is shown for each member. D, Electropherograms for the M144V site. E, Representative
results (from test primers 3, 4, 6, and 10) of the PCR-based deletion mapping of the C7orf11 locus in patient 6474 (lane C, control; lane P,
patient 6474). Unblackened triangles indicate the 704-bp fragment amplified by control primer DJg5/g6. The blackened triangles indicate the
fragment amplified by a test primer pair. The cycling conditions were initial denaturation at 94�C for 3 min followed by 36 cycles of denaturation
at 94�C for 30 s, annealing at 58�C for 30 s, and extension at 72�C for 75 s. Detailed information for the 11 test primers pairs and the control
primer pair is available in table A1 (online only).





Reports 513

Figure 2 A, The human C7orf11 protein. The glycine/proline–rich region is shown in green (the low-complexity regions detected by the
BLASTP program are in light green). There are two highly conserved C terminal regions (CR1 and CR2) among the candidate orthologues.
The evolutionary tree (middle) was drawn by the ClustalX program (Thompson et al. 1997). The protein sequences used for phylogenetic
analysis are human C7orf11 (NCBI accession number NP_619646) and orthologues from chimpanzee (Ensembl accession number
ENSPTRP00000032652), mouse (NCBI accession number BAB27916), rat (Ensembl accession number ENSRNOP00000018746), chicken
(Ensembl accession number ENSGALP00000020100), frog (Xenopus tropicalis [NCBI accession number NP_989025]), pufferfish (Tetraodon
nigroviridis [NCBI accession number CAF91712]), fruit fly (Drosophila melanogaster [NCBI accession number NP_648690]), and mosquito
(Anopheles gambiae [NCBI accession number XP_318005]). Deduced protein sequences were derived from cDNA sequences from zebrafish
(Danio rerio [GenBank accession number BC062385]) and pig (GenBank accession number BP456435). The dog protein sequence was predicted
from the genomic DNA sequence (see UCSC Genome Browser Web site). For each species, the overall amino acid similarity with the human
protein sequence, the percentage ratio of glycine/proline content in the region from the N terminus to CR1, and the presence (�) or absence
(�) of CR1 and CR2 are shown. Multiple sequence alignments for CR1 and CR2 are at bottom. The position of M144V in CR2 is indicated
by a red asterisk (*). Identical and similar amino acids are highlighted in dark and light blue, respectively. B, Subcellular localization assay.
Transiently expressed Myc-tagged C7orf11 in human cultured cells (transformed human embryonic kidney cells [HEK293] and SV40-transformed
WI38 human embryonic fibroblasts [VA13]) was examined by immunostaining, by use of anti-Myc antibody and a secondary antibody conjugated
with fluorescein isothiocyanate (FITC). Bright-field (BF), 4’-6-diamidino-2-phenylindole (DAPI), FITC, and the merged image of DAPI and FITC
signals are shown for each cell line. The Myc-tagged cDNA construct for C7orf11 was generated by inserting the coding region of C7orf11
(nucleotides 51–590 of mRNA) in pcDNA3.1� Myc-His A (Invitrogen). DNA transfection was performed using Lipofectamine Plus (Invitrogen).
Two days after transfection, cells were washed in PBS and were fixed in 50% acetone plus 50% methanol at �20�C for 15 min. The samples
were blocked with 10% BSA in PBS (blocking buffer) for 1 h and were incubated in blocking buffer containing anti-Myc antibody (Santa Cruz
Biotechnology) for 45 min. Cells were washed three times with PBS, were incubated with FITC-conjugated anti-mouse IgG antibody for 30
min, and were washed three times with PBS. After DAPI staining, the samples were analyzed by deconvolution microscopy (Zeiss). C, In situ
RNA hybridization for C7orf11 on human fetal skin tissue. A 556-bp cDNA fragment (corresponding to nucleotides 303–858 of mRNA) was
subcloned in pCR-Script (Stratagene) and was used as template DNA to synthesize [35S]UTP-labeled riboprobes. [35S]UTP-labeled riboprobes
(sense and antisense) were hybridized to the sections. Radioactive signals were detected by autoradiography with 38 d of exposure. Slides were
counterstained with hematoxylin-eosin and were photographed under dark-field (DF) and bright-field (BF) illumination. The signal detected in
epidermis and hair follicles is specific to the antisense probe. The detail conditions used for hybridization, washing, and signal detection were
described elsewhere (Saarialho-Kere et al. 1992). D, Normal level of TFIIH in fibroblast cells from one of the Moroccan siblings with the 2-
bp deletion. Mixed DAPI/phase contrast image (top) showing a normal (with large beads) and TTD (with small beads) cells. Immunofluorescence
with anti-XPB antibody (bottom). For exact quantitative comparison of fluorescence signals between normal and TTD fibroblasts without slide-
to-slide variability, two types of fibroblasts were preloaded with cytoplasmic plastic beads of different sizes (large beads for normal and small
beads for TTD) and then were mixed, cultured overnight, and processed for immunofluorescence.

Chromosome 7 Annotation Project [see Web site]) by
DNA sequencing and identified three homozygous se-
quence variations in the affected members of family E
(fig. 1C): a TrC variant in intron 7 of C7orf10, a GrA
variant in exon 1 of CDC2L5 causing an arginine-to-
lysine substitution (R21K), and an ArG variant in exon
2 of C7orf11 causing a methionine-to-valine substitution
(M144V). The first two sequence variations were ex-
cluded from further analysis, because the same genotype
was found in either normal controls or the unaffected
parents in family E. We have shown elsewhere that
C7orf11 encodes a 179-aa protein of unknown function
(Nakabayashi et al. 2002) and that it is variably ex-
pressed in many tissues, including fibroblasts and brain.
By sequencing all available members of the Amish kin-
dred, we confirmed that all 13 affected cases were ho-
mozygous for the ArG variant and that 26 unaffected
members were either heterozygous carriers (18/26) or
homozygous for the normal allele (8/26) (fig. 1C and
1D). We genotyped 148 controls (296 chromosomes),
including 48 unrelated Amish individuals, and confirmed
cosegregation of the M144V variant in only carrier or
disease chromosomes.

We then examined C7orf11 in 12 additional cases of
nonphotosensitive TTD and found two deleterious

homozygous deletions. In siblings of Moroccan origin
with TTD (Przedborsk et al. 1990), we found a 2-bp
homozygous deletion in exon 1 (nucleotides 187 and
188 of C7orf11 mRNA [GenBank accession number
NM_138701]) (data not shown), which predicts a 57-
aa truncated protein. In another case—an Italian patient
with TTD and severe nervous-system impairment (pa-
tient 6474) (Rizzo et al. 1992)—our attempts to amplify
the coding regions of C7orf11 failed. By multiplex PCR
using a primer pair that amplifies a 704-bp control frag-
ment, we determined that part of exon 1 and the entire
exon 2 of C7orf11 were homozygously deleted, whereas
the flanking genes (CDC2L5 and C7orf10) were not (fig.
1B and 1E). These patients with homozygous deletions
are likely to be genetically null for C7orf11, which might
explain their more-severe neurological phenotype in
comparison with that of the patients with ABHS. We
did not find any mutations in the two exons and 5′ up-
stream region of C7orf11 in the other 10 cases of non-
photosensitive TTD, including two cases of Sabinas syn-
drome and one case of Pollitt syndrome, which suggests
that genetic heterogeneity exists in nonphotosensitive
TTD. The fibroblasts derived from all but two patients
with Sabinas syndrome were tested for UV sensitivity by
use of various NER parameters, including unscheduled



Table 1

Clinical Features and C7orf11 Mutations in Patients with Nonphotosensitive TTD

STUDY

FINDINGa FOR

Isolated TTDb Sabinas Syndrome ABHS Moroccan Siblings Pollitt Syndrome
Patient 6474

(Present Study) IBIDSb

Clinical features:
Hair defect � � � � � � �
Nail dystrophy � � � � � � �
Mental retardation � (IQ 80) � (IQ 50–60) �c (IQ 90) � (IQ 25–40) � � �
Growth retardation � � �c � � � �
Ichthyosis � � � � � �d �
Decreased fertility � �e �f

Other features Ataxia Ataxia, dental caries Severe nervous-
system impairment

Cataract, collodion
skin at birth

UV sensitivity of fibroblastsg ND ND ND No UV sensitivity No UV sensitivity No UV sensitivity ND
Mutations in C7orf11h ND No mutation 480ArG (M144V) 187_188delGG No mutation Deletion: part exon 1

and entire exon 2
ND

Reference Alfandari et al. 1993 Howell et al. 1981 Baden et al. 1976;
Jackson et al. 1974

Przedborski et al. 1990 Pollitt et al. 1968 Rizzo et al. 1992;
Stefanini et al. 1992

Jorizzo et al. 1982

a ND p not determined; � p presence; � p absence.
b The isolated TTD cases and the ichthyosis, brittle hair, impaired intelligence, decreased fertility, and short stature (IBIDS) cases were not analyzed in this study but are included in the

table to show the extent of the spectrum of TTD symptoms.
c Mild.
d Ichthyosiform areas present only on the lower limbs.
e Male only.
f Gonadal dysfunction tested.
g UV sensitivity tests were performed using various NER parameters, including unscheduled DNA synthesis (global NER), recovery from transcription inhibition (transcription-coupled

NER), and overall clonogenic cell survival after UV exposure.
h GenBank accession number NM_138701.



Reports 515

DNA synthesis, recovery from transcription inhibition,
and overall clonogenic cell survival after UV exposure.
Microsatellite analysis also excluded the 2-Mb C7orf11
locus from involvement in Sabinas syndrome. Therefore,
we have designated C7orf11 with the symbol TTDN1
(TTD nonphotosensitive 1).

We identified predicted proteins with sequence simi-
larity to human C7orf11 in six mammalian species as
well as chicken, frog, fish, and insects, but not in lower
eukaryotic species (C. elegans and yeast). The first two-
thirds of the human C7orf11 protein is remarkably gly-
cine/proline–rich (45% in 125 aa), and this feature is
more evident in higher eukaryotic species (fig. 2A). There
are two highly conserved regions: CR1, conserved from
zebrafish to human, and CR2, conserved from mosquito
to human (fig. 2A). The mutant M144V found in pa-
tients with ABHS is located in the three amino acid res-
idues (SML) in CR2 that are conserved in all species.
To examine the subcellular localization of C7orf11, we
transfected Myc-epitope–tagged protein into cultured
mammalian cells and found that it was predominantly
expressed in the nucleus (fig. 2B); the pattern of the Myc-
epitope–mutated protein was indistinguishable from the
wild type (data not shown). We performed in situ RNA
hybridization analysis for C7orf11 in human fetal skin
tissue and found that it was expressed in epidermis and
hair follicles, consistent with presentation of the phe-
notype (fig. 2C). C7orf11 expression was not clearly
detected in dermis by in situ hybridization, but it was
found by RT-PCR in fibroblast cells.

To examine whether C7orf11 mutations affect TFIIH
cellular concentration, we performed comparative im-
munofluorescence analysis, using antibody against the
xeroderma pigmentosum group B protein (XPB) (a core
component of TFIIH), and found that the TFIIH levels
in normal controls and in fibroblasts from a patient with
TTD (one of the Moroccan siblings with the 2-bp de-
letion) are the same (fig. 2D). This result, combined with
the observation that mutations could not be detected in
any of TFIIH subunits and with the genetic mapping
data (not shown), suggests that the defect in nonpho-
tosensitive TTD is independent of TFIIH action.

To our knowledge, C7orf11 is the first gene identified
as mutated in patients with nonphotosensitive TTD.
Since these mutations were found in only a subset of
nonphotosensitive TTD cases, it is likely that there is
more than one disease-causing gene, as was found for
photosensitive TTD. Photosensitive TTD is caused by
mutations in genes encoding subunits (XPD, XPB, and
TTD-A) of the TFIIH complex that functions in tran-
scription and DNA repair. Since there is an absence of
cutaneous photosensitivity in the patients with C7orf11
mutations and since the protein demonstrates a nuclear
localization, it is possible that C7orf11 may have a role
in transcriptional processes but have no role in DNA

repair. Moreover, the brittle hair observed in patients
with TTD is thought to result from the reduced expres-
sion of high-sulfur proteins (intermediate keratin fil-
aments and matrix proteins) in the late stage of kera-
tinocyte differentiation (Bergmann and Egly 2001).
Genes in these pathways and/or proteins associated with
C7orf11 would be the primary candidates for involve-
ment in other nonphotosensitive TTD cases.

Acknowledgments

We thank Alli Tallqvist for skillful technical assistance in
RNA in situ hybridization experiments. We acknowledge The
Centre for Applied Genomics, the Genome Canada/Ontario
Genome Institute, the Hospital for Sick Children Foundation,
the Association Française contre les Myopathies, and the
Dykstra Foundation in Detroit (grant to C.E.J.). S.W.S. is an
Investigator of the Canadian Institutes of Health Research, a
Scholar of the McLaughlin Centre for Molecular Medicine,
and an International Scholar of the Howard Hughes Medical
Institute.

Electronic-Database Information

Accession numbers and URLs for data presented herein are
as follows:

The Chromosome 7 Annotation Project, http://www.chr7.org/
(for seven candidate genes on 7p14)

Ensembl, http://www.ensembl.org/ (for proteins from
chimpanzee [accession number ENSPTRP00000032652],
rat [accession number ENSRNOP00000018746], and
chicken [accession number ENSGALP00000020100])

GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ (for
human C7orf11 mRNA [accession number NM_138701]
and cDNA sequences from zebrafish [accession number
BC062385] and pig [accession number BP456435])

NCBI, http://www.ncbi.nlm.nih.gov/ (for human C7orf11 [ac-
cession number NP_619646] and orthologues from mouse
[accession number BAB27916], frog [accession number
NP_989025], pufferfish [accession number CAF91712],
fruitfly [accession number NP_648690], and mosquito [ac-
cession number XP_318005])

Online Mendelian Inheritance in Man (OMIM), http://www
.ncbi.nlm.nih.gov/Omim/ (for Amish brittle-hair syndrome,
Sabinas syndrome, and Pollitt syndrome)

UCSC Genome Browser, http://genome.ucsc.edu/

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