doi:10.1086/383205


777

Letter to the Editor

Am. J. Hum. Genet. 74:777–780, 2004

Novel Truncating Mutations in the Polyglutamine
Tract Binding Protein 1 Gene (PQBP1) Cause
Renpenning Syndrome and X-Linked Mental
Retardation in Another Family with Microcephaly

To the Editor:
Although several families with X-linked mental retar-
dation (XLMR) (Martin and Bell 1943; Allan et al.
1944; Bickers and Adams 1949; Losowsky 1961) had
been reported prior to the Renpenning study (Renpen-
ning et al. 1962), the term “Renpenning syndrome”
(MIM 309500) came into general use for XLMR, en-
compassing both syndromic and nonsyndromic forms
(Richards 1970; Gerrard and Renpenning 1974; Steele
and Chorazy 1974; Howard-Peebles et al. 1979; Jen-
nings et al. 1980; McLaughlin and Kriegsmann 1980;
Proops and Webb 1981; Archidiacono et al. 1987). Ren-
penning et al. (1962) described a Mennonite family in
which 20 males in three generations had mental retar-
dation (MR). Manifestations in affected males included
microcephaly, short stature, and small testes; carrier fe-
males appeared normal.

Previously, we reported linkage of the family described
by Renpenning and colleagues (1962) to Xp11.2–p11.4
(Stevenson et al. 1998) (fig. 1A). In addition, we iden-
tified another family exhibiting microcephaly and MR
(fig. 1B). Herein, we report truncating mutations in the
polyglutamine tract binding protein 1 (PQBP1) gene
(MIM 300463) in both families.

Mutations in the gene that codes for the polyglutam-
ine tract binding protein 1, located in Xp11.2, have been
found in patients with Sutherland-Haan syndrome
(MIM 309470), cerebropalatocardiac (Hamel) syn-
drome, and MRX55, as well as in two other families
(Kalscheuer et al. 2003). PQBP1 consists of six exons
that code for a protein of 265 amino acids. A WW do-
main is encoded by the amino acid positions 47–78,
which has been shown to play an important role in reg-
ulation of transcription activity by interacting with the
carboxy-terminal domain of the RNA polymerase II (Su-
dol et al. 2001). Additionally, a polyglutamine-binding
region (in the polar-amino-acid–rich domain [PRD]), a
DR/ER stretch, is encoded by exon 4 and is involved in

transcriptional control by binding to the polyQ region
of the transcription factor BRN2 that silences transcrip-
tion (Sudol et al. 2001). The unifying findings in these
patients with XLMR are microcephaly and short stature.
A variety of other manifestations, including ocular co-
lobomas, cleft palate, cardiac defects, small testes, anal
anomalies, and spasticity, have occurred in a minority
of patients. So far, all mutations have been found in exon
4 (GenBank accession number NM_005710), where
they are predicted to disrupt the polyglutamine-binding
PRD and to shorten the protein (Kalscheuer et al. 2003).

The mutation in the family described by Renpenning
and colleagues (1962) is an insertion of one cytosine
residue in exon 5 (c.641insC). This frameshift insertion
causes a premature stop codon at amino acid position
226 (fig. 1A). The observed mutation was found in all
available males with MR in the pedigree, including one
male who was found to have milder cognitive impair-
ment ( ) (individual V-18) (fig. 1A). X-chro-IQ p 70
mosome inactivation in carrier females was not skewed.
In the other family presenting with MR and microceph-
aly (K9008), we detected a novel AG dinucleotide de-
letion at the end of exon 4 (c.575_576delAG), causing
a frameshift and introducing a new stop codon at amino
acid position 198 (fig. 1B). Neither of these truncating
alterations was found in 200 X chromosomes from un-
affected males.

In contrast to the previously found mutations in the
PQBP1 gene that are all located in the middle of exon
4, these mutations, at either the end of exon 4 or exon
5, do not affect the PRD (fig. 2). Taking into account
all mutations in the PQBP1 gene that have been de-
scribed here and by Kalscheuer et al. (2003), two groups
of mutations can be classified: (1) deletions or insertions
of AG nucleotides affecting the DR/ER repeat in the PRD
and (2) frameshift aberrations leaving the PRD undis-
turbed (fig. 2). However, the common clinical manifes-
tations, MR, microcephaly, and short stature, are present
in all families. Therefore, it might be of interest to de-
termine whether the PRD in the truncated proteins from
the family described by Renpenning and colleagues
(1962) and the K9008 family still interacts with BRN2
or whether the loss of the last 67 or 40 amino acids
disturbs this function. Alternatively, the interaction with
other, yet-unknown proteins might be disrupted.

Advances in clinical delineation and in molecular un-



Figure 1 Families with novel mutations in the PQBP1 gene. A, Partial pedigree of the family described by Renpenning and colleagues
(1962) (family K8110), with the c.641insC mutation. Numbering of the pedigree is consistent with that published elsewhere (Stevenson et al.
1998). The c.641insC mutation, highlighted and indicated by the arrow, is present in exon 5 and is very close to the exon/intron boundary.
The shaded region shows the intronic sequence. This mutation causes a frameshift in the C2 domain, resulting in the premature truncation of
the protein. B, Pedigree of family K9008, with the c.575_576delAG mutation in the NLS (nuclear localization signal) domain. This deletion is
in exon 4 (highlighted in yellow) and occurs very close to the exon/intron boundary (sequence contributed from the intron is shaded). This
mutation causes a frameshift and results in a premature truncation of the PQBP1 protein, which lacks the C2 domain.



Letter to the Editor 779

Figure 2 Truncating mutations in the PQBP1 protein. This figure shows the structure of the PQBP1 protein with the WW domain, the
PRD with DR/ER repeats, the NLS domain, and the C2 domain (modified from Waragai et al. 1999). The novel mutations reported in this
study (c.575_576delAG and c.641insC) are in boldface. The three different mutations in the DR/ER domain reported by Kalscheuer et al. (2003)
are in italics.

derstandings of XLMR have now identified 120 syn-
dromic forms of XLMR and 81 families with nonsyn-
dromic XLMR (Stevenson et al. 2003). To date, mu-
tations in 47 genes have been linked to XLMR. Of these
47 genes, 29 have been linked exclusively to syndromic
XLMR, 11 exclusively to nonsyndromic XLMR, and 7
to both (Stevenson and Schwartz 2002).

With the exception of Allan-Herndon syndrome
[MIM 309600], all XLMR syndromes reported prior to
the discovery of the fragile X syndrome [MIM 309550]
have now been linked to mutations of a specific gene.
Identification of a PQBP1 mutation in Renpenning syn-
drome and other XLMR syndromes (Kalscheuer et al.
2003) exemplifies the lumping of XLMR syndromes that
has become justified on the basis of molecular studies
(Stevenson 2000). As MR, microcephaly, and short stat-
ure seem to be consistent findings among individuals
with PQBP1 mutations, patients with these findings
should be included in any testing scheme. In a South
Carolina study of mental retardation, among 4,008
males with MR of unknown cause, 486 (12%) have
microcephaly, 350 (9%) have short stature, and 128
(3%) have both (R.E.S., unpublished data). Hence, mi-
crocephaly is the most common physical finding among
males with MR of unknown cause (Stevenson et al.
2003) and is a reliably ascertained finding that may be
useful in the selection of cases for PQBP1 mutation
testing.

Acknowledgments

The authors express their gratitude to the families involved
in this research and to Julianne Collins, Ph.D., Sharon Card-
well, Celeste Krauss, M.D., Martha MacMillin, and Lynda
Holloway for clinical information and assistance. This work
was supported by the German Ministry for Research and Ed-
ucation (BMBF, 01KW9974), the European Community
(QLG2-CT-1999-00791) (A.M.), grants from the National In-

stitutes of Health (HD26208 [C.E.S.] and MH57840 [R.E.S.]),
a grant from the Belgian National Fund for Scientific Re-
search—Flanders (FWO), and the Interuniversity Attraction
Poles Program (IUAP-V) (R.F.K.). This study is dedicated to
the memory of Ethan Francis Schwartz (1996–1998).

CLAUS LENSKI,1 FATIMA ABIDI,2 ALFONS MEINDL,1

ALICE GIBSON,3 MATTHIAS PLATZER,4

R. FRANK KOOY,5 HERBERT A. LUBS,6

ROGER E. STEVENSON,2 JULIANE RAMSER,1 AND
CHARLES E. SCHWARTZ2

1Department of Medical Genetics at the Ludwig-
Maximilians-University, Munich; 2J.C. Self Research
Institute, Greenwood Genetic Center, Greenwood, SC;
3Royal University Hospital, Saskatoon, Canada;
4Institute for Molecular Biotechnology, Jena,
Germany; 5Department of Medical Genetics,
University of Antwerp, Antwerp, Belgium; and
6Mailman Center for Child Development, University
of Miami School of Medicine, Miami, FL

Electronic-Database Information

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

GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ (for PQBP1
[accession number NM_005710])

Online Mendelian Inheritance in Man (OMIM), http://www
.ncbi.nlm.nih.gov/Omim/ (for Renpenning syndrome,
PQBP1, Sutherland-Haan syndrome, Allan-Herndon syn-
drome, and fragile X syndrome)

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780 Letter to the Editor

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Address for correspondence and reprints: Dr. Charles E. Schwartz, J.C. Self
Research Institute, Greenwood Genetic Center, 1 Gregor Mendel Circle, Green-
wood, SC 29646. E-mail: schwartz@ggc.org

� 2004 by The American Society of Human Genetics. All rights reserved.
0002-9297/2004/7404-0020$15.00


	Novel Truncating Mutations in the Polyglutamine Tract Binding Protein 1 Gene (PQBP1 )Cause Renpenning Syndrome and X-Linked Mental Retardation in Another Family with Microcephaly
	Acknowledgments
	References