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To the Editor: Although several families with X-linked mental retardation (XLMR) (Martin and Bell 1943; Allan et al. 1944; Bickers and Adams 1949; Losowsky 1961) had been reported prior to the Renpenning study (Renpenning et al. 1962), the term “Renpenning syndrome” (MIM 309500) came into general use for XLMR, encompassing both syndromic and nonsyndromic forms (Richards 1970; Gerrard and Renpenning 1974; Steele and Chorazy 1974; Howard-Peebles et al. 1979; Jennings et al. 1980; McLaughlin and Kriegsmann 1980; Proops and Webb 1981; Archidiacono et al. 1987). Renpenning et al. (1962) described a Mennonite family in which 20 males in three generations had mental retardation (MR). Manifestations in affected males included microcephaly, short stature, and small testes; carrier females 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 identified 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. 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 ... Mutations in the gene that codes for the polyglutamine tract binding protein 1, located in Xp11.2, have been found in patients with Sutherland-Haan syndrome (MIM 309470), cerebropalatocardiac (Hamel) syndrome, 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 domain is encoded by the amino acid positions 47–78, which has been shown to play an important role in regulation of transcription activity by interacting with the carboxy-terminal domain of the RNA polymerase II (Sudol 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 transcription (Sudol et al. 2001). The unifying findings in these patients with XLMR are microcephaly and short stature. A variety of other manifestations, including ocular colobomas, 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 {"type":"entrez-nucleotide","attrs":{"text":"NM_005710","term_id":"74027245","term_text":"NM_005710"}}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 impairment (IQ=70) (individual V-18) (fig. 1A). X-chromosome inactivation in carrier females was not skewed. In the other family presenting with MR and microcephaly (K9008), we detected a novel AG dinucleotide deletion 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 unaffected 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 described 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 undisturbed (fig. 2). However, the common clinical manifestations, MR, microcephaly, and short stature, are present in all families. Therefore, it might be of interest to determine 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. 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 ... Advances in clinical delineation and in molecular understandings of XLMR have now identified 120 syndromic forms of XLMR and 81 families with nonsyndromic XLMR (Stevenson et al. 2003). To date, mutations 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 syndrome 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 stature 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, microcephaly 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.

X-linked cone-rod dystrophy (COD1) is a retinal disease that primarily affects the cone photoreceptors; the disease was originally mapped to a limited region of Xp11.4. We evaluated the three families from our original study with new markers and clinically reassessed all key recombinants; we determined that the critical intervals in families 2 and 3 overlapped the RP3 locus and that a status change (from affected to probably unaffected) of a key recombinant individual in family 1 also reassigned the disease locus to include RP3 as well. Mutation analysis of the entire RPGR coding region identified two different 2-nucleotide (nt) deletions in ORF15, in family 2 (delAG) and in families 1 and 3 (delGG), both of which result in a frameshift leading to altered amino acid structure and early termination. In addition, an independent individual with X-linked cone-rod dystrophy demonstrated a 1-nt insertion (insA) in ORF15. The presence of three distinct mutations associated with the same disease phenotype provides strong evidence that mutations in RPGR exon ORF15 are responsible for COD1. Genetic heterogeneity was observed in three other families, including the identification of an in-frame 12-nt deletion polymorphism in ORF15 that did not segregate with the disease in one of these families.