In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.

Evidence from many sources suggests that similar phenotypes are begotten by functionally related genes. This is most obvious in the case of genetically heterogeneous diseases such as Fanconi anemia, Bardet-Biedl or Usher syndrome, where the various genes work together in a single biological module. Such modules can be a multiprotein complex, a pathway, or a single cellular or subcellular organelle. This observation suggests a number of hypotheses about the human phenome that are now beginning to be explored. First, there is now good evidence from bioinformatic analyses that human genetic diseases can be clustered on the basis of their phenotypic similarities and that such a clustering represents true biological relationships of the genes involved. Second, one may use such phenotypic similarity to predict and then test for the contribution of apparently unrelated genes to the same functional module. This concept is now being systematically tested for several diseases. Most recently, a systematic yeast two-hybrid screen of all known genes for inherited ataxias indicated that they all form part of a single extended protein-protein interaction network. Third, one can use bioinformatics to make predictions about new genes for diseases that form part of the same phenotype cluster. This is done by starting from the known disease genes and then searching for genes that share one or more functional attributes such as gene expression pattern, coevolution, or gene ontology. Ultimately, one may expect that a modular view of disease genes should help the rapid identification of additional disease genes for multifactorial diseases once the first few contributing genes (or environmental factors) have been reliably identified.

We review 43 p atie n ts (15 new, 28 literature) w ith the branchio-oculo-facial (BOF) syn drome, w h ic h has a d istin ctiv e phenotype ran g in g from m ild to severe forms, consist in g of eye, ear, oral, a n d craniofacial anom alies. V irtu a lly u b iq u ito u s and possibly pathognom onic are the cervical/infra-auricu la r sk in defects. M uch less common are supra-auricular defects occurring as iso late d anom alies or w ith cervical defects. Re gardless of lo catio n , these lesions may have aplastic, "hem angiom atous," or otherwise abnorm al overlying skin, and d ra in in g sinus fìstulae. R e n a l m alfo rm atio ns are frequent, b u t congenital h e a rt a n d central nervous system defects are rare* Psychomotor per form ance is u s u a lly norm al, b u t develop m ent delays, h y p o to n ia , and visual, hearing, and speech problem s are common. Autoso m al d o m in a n t in h e rita n c e seems likely. Overlap betw een the B O F and branchio-otorenal syndromes has been observed, b u t elu cidation o f its m o le cu lar basis is not yet available. This article also discusses 5 p a tients w ith aty p ical m anifestations consid ered to be possibly affected or probably u n affected, w ho are sufficiently unusual to be excluded from the fin a l data analysis.

Inherited retinal dystrophies represent the most important cause of vision impairment in adolescence, affecting approximately 1 out of 3000 individuals. Mutations of the photoreceptor-specific gene ABCA4 (ABCR) are a common cause of retinal dystrophy. A number of mutations have been repeatedly reported for this gene, notably the 2588G4C mutation which is frequent in both patients and controls. Here we ascertained the frequency of the 2588G4C mutation in a total of 2343 unrelated random control individuals from 11 European countries and 241 control individuals from the US, as well as in 614 patients with STGD both from Europe and the US. We found an overall carrier frequency of 1 out of 54 in Europe, compared with 1 out of 121 in the US, confirming that the 2588G4C ABCA4 mutation is one of the most frequent autosomal recessive mutations in the European population. Carrier frequencies show an increasing gradient in Europe from South-West to North-East. The lowest carrier frequency, 0 out of 199 (0%), was found in Portugal; the highest, 11 out of 197 (5.5%), was found in Sweden. Haplotype analysis in 16 families segregating the 2588G4C mutation showed four intragenic polymorphisms invariably present in all 16 disease chromosomes and sharing of the same allele for several markers flanking the ABCA4 locus in most of the disease chromosomes. These results indicate a single origin of the 2588G4C mutation which, to our best estimate, occurred between 2400 and 3000 years ago.European Journal of Human Genetics (2002) 10, 197 ± 203 ã 2002 Nature Publishing Group All rights reserved 1018-4813/02 $25.00 www.nature.com

To define the PKD1 locus further, the gene involved in the most frequent form of adult polycystic kidney disease, probes from 16 polymorphic loci were mapped on 16pI3.1-pter with the combined use of cell lines containing rearranged chromosomes and family studies. Five breakpoints in the distal part of 16p arbitrarily subdivided the loci into five groups. By analysing 58 recombination events among 259 informative meioses in 12 large families with PKD, we were able to construct a linkage map for the distal part of 16p. The order of the markers obtained with chromosomal rearrangements was confirmed by the family studies. The D16S85 locus near a globin, D16S21, and D16S83 map distal, ortelomeric, toPKDI. The polymorphic red cell enzyme phosphoglycolate phosphatase (PGP), D16S84, D16S259, and D16S246 showed no recombination with PKDI. The remaining nine RFLPs all map proximal to the PKD1 gene. By cosmid walking, additional RFLPs were detected at the D16S21 locus. A single intrahaplotype recombination observed defines the orientation of D16S21 relative to PKDL.The new polymorphisms are valuable for presymptomatic and prenatal diagnosis of PKD1. Furthermore, our map is both a good starting point for the physical map of 16p and a useful tool for the isolation of the PKD1 gene.