Genotype-phenotype studies in three families with mutations in the polyglutamine-binding protein 1 gene (PQBP1).

Recently, the polyglutamine-binding protein 1 (PQBP1) gene was found to be mutated in five of 29 families studied with X-linked mental retardation (XLMR) linked to Xp. The reported mutations include duplications or deletions of AG dinucleotides in the fourth coding exon that resulted in shifts of the open reading frame. Three of the five families with mutations in this newly identified XLMR gene have been reported previously. We characterized the phenotypic and neuropsychological features in the two unpublished families with aberrations in PQBP1 and in a family reported 10 years ago. In total, seven patients diagnosed with aberrations in this gene were examined, including a newly identified patient at 18 months of age. Additionally, the features were compared to those reported in the literature of three other families, comprising MRXS3 (Sutherland-Haan syndrome) MRX55 and MRXS8 (Renpenning syndrome). Characteristics seen in these patients are microcephaly, lean body habitus, short stature, striking facial appearance with long narrow faces, upward slant of the eyes, malar hypoplasia, prognathism, high-arched palate and nasal speech. In addition, small testes and midline defects as anal atresia or imperforate anus, clefting of palate and/or uvula, iris coloboma and Tetralogy of Fallot are seen in several patients. These observations contribute to the phenotypic knowledge of patients with PQBP1 mutations and make this XLMR syndrome well recognizable to clinicians.

Benign familial hematuria due to mutation of the type IV collagen alpha4 gene.

Benign familial hematuria (BFH) is characterized by autosomal dominant inheritance, thinning of the glomerular basement membrane (GBM) and normal renal function. It is frequent in patients with persistent microscopic hematuria, but cannot be clinically differentiated from the initial stages of Alport syndrome, a severe GBM disorder which progresses to renal failure. We present here linkage of benign familial hematuria with the COL4A3 and COL4A4 genes at 2q35-37 (Zmax = 3.58 at theta = 0.0). Subsequently, a glycine to glutamic acid substitution was identified in the collagenous region of the COL4A4 gene. We conclude that type IV collagen defects cause both benign hematuria and Alport syndrome. Furthermore, our data suggest that BFH patients can be carriers of autosomal recessive Alport syndrome.

Familial Angelman syndrome with a crossover in the critical deletion region.

More than two thirds of the patients with Angelman syndrome (AS) carry a deletion or other chromosomal abnormality in the 15q11-13 region. A much less frequent cause (4%) is paternal uniparental disomy of the entire chromosome. In general no abnormalities are detectable in familial cases and an inherited submicroscopic deletion was described only once. Here a familial case of 2 sibs with AS is reported. No major cytogenetic or molecular abnormality was identified, but a recombination event had occurred in the AS critical region. The AS locus, D15S113, D15S10, D15S11, and D15S18 mapped proximal and the GABRB3 gene, D15S97, the GABRA5 gene, and D15S12 distal to the crossover site. This recombination within the AS critical region confirmed the exclusion of GABRB3 as a candidate gene for AS. Other markers and candidate genes can be tested genetically as well for a possible role in AS.