Disease gene mapping

(Prepared by John Carpten)

Several human genetic disorders were mapped to chromosome 1 and a number of previously mapped disease loci were genetically refined since the last workshop report. In addition a number of disease genes and mutations were identified since the last workshop. Detailed information can be found for most of these disorders using the Online Mendelian Inheritance In Man (OMIM) resource. Listed here is a brief mapping update for these disorders. OMIM reference numbers are provided where available (Tables 6 and 7).

Muscle-eye-brain disease (OMIM# 253280). Cormand and coworkers mapped the MEB locus to 1p32-p34 by linkage analysis and homozygosity mapping in eight families (Cormand et al., 1999).

Psoriasis susceptibility 4 (OMIM #603935). A new locus for psoriasis, a common skin disorder, was genetically mapped to chromosome 1cen-q21 (Capon et al., 2000, this workshop). This study noted that genetic heterogeneity is evident, as there are also reports of linkage to 6p and 17q.

Hemochromatosis (OMIM #602390). Mutations in the HFE gene on chromosome 6p lead to common hereditary hemochromatosis. Roetta and colleagues mapped an autosomal recessive juvenile form of hemochromatosis to 1q21, near D1S498 and D1S2344, in a set of non-6p-linked, non-HFE families with hemochromatosis. The region was refined by homozygosity mapping to a 4 cM interval (Roetto et al., 1999). A positional candidate gene known as ZIRTL that encodes for a divalent metal ion-transporter was excluded by mutational analysis (Roetto et al., 2000).

Schizophrenia susceptibility locus 9 (OMIM #604906). Two groups (Meissner et al., 1999; Stober et al., 2000) investigated the association between the polymorphic CAG repeat in the neuronal potassium channel gene KCNN3/hSKCa3 (1q21.3) and an increased susceptibility to schizophrenia. No evidence of association was seen. Results of a genome-wide scan revealed linkage to 1q21-q22 in 22 extended families with high rates of schizophrenia (Brzustowicz et al., 2000).

Stress-induced polymorphic ventricular tachycardia (OMIM #604772). Swan and colleagues mapped an autosomal dominant cardiac syndrome causing stress-induced polymorphic ventricular tachycardia to1q42-q43 in two unrelated families (Swan et al., 1999).

In this workshop, two new disease loci localizing to chromosome 1 were reported. Fernandez and coworkers reported linkage of a new locus for progressive familial heart block type II (OMIM #140400) to 1q32-q41 in a single family from South Africa. Hoffmann and collaborators mapped Pelger-Huet anomaly (OMIM #169400), a benign disorder altering granulocyte morphology, to a region on 1q41-q43.

In addition to new chromosome 1 mapped genetic disorders, progress was made towards the genetic refinement and linkage confirmation of diseases previously mapped to chromosome 1. These include:

Autosomal recessive Charcot-Marie-Tooth type 1b (OMIM #118200). A genome-wide scan was performed on a large consanguineous Moroccan family with nine affected sibs after exclusion of other known CMT loci (Bouhouche et al., 1999). Bouhouche and colleagues found linkage to markers in a 1.7 cM region at1q21-q23 for the axonal form of autosomal recessive CMT.

Combined Hyperlipidemia (OMIM #602491). Coon and collaborators (Coon et al., 2000) confirmed linkage of hyperlipidemia to markers on chromosome 1 using a total of 71 families. They performed 2-locus analysis with D1S104 and a marker on chromosome 11 that resulted in a positive LOD score suggesting possible heterogeneity in hyperlipidemia. Pei and colleagues also obtained positive linkage results on 1q21-q23 for hyperlipidemia, assuming heterogeneity, using a set of families of German or Chinese descent (Pei et al., 2000).

Van der Woude syndrome (OMIM #119300). Beiraghi and colleagues (Beiraghi et al., 1999) confirmed linkage of autosomal dominant Van der Woude syndrome to 1q32-q41 in four multiplex families and reported evidence of a possible ancestral haplotype. Houdayer and coworkers (Houdayer et al., 1999) also confirmed linkage of Van der Woude syndrome to the same region using five independent families.

At this workshop, refined mapping of two loci were reported, autosomal dominant cholesterolimia (OMIM #603776) at 1p32-p34 (Varret et al.) and familial cold urticaria (OMIM #120100) at 1q44 (Hoffman et al.).

Several disease-causing mutations were identified for genetic diseases mapping to chromosome 1 since the previous workshop report. These include:

Camptodactyly-arthropathy-coxa vara-pericarditis/CACP Proteoglycan 4 (OMIM #604283). Mutations in a secreted proteoglycan (PRG4, previously known as megakaryocyte growth and stimulating factor) were found in patients with this autosomal recessive disorder (Marcelino et al., 1999). Marcelino and colleagues reported six homozygous truncating mutations in six independent families, suggesting that the disease is caused by loss of function of the PRG4 gene.

Autosomal recessive steroid-resistant nephrotic syndrome (OMIM #600995). Recently, mutations in the NPHS2 gene were found in patients with autosomal recessive steroid-resistant nephrotic syndrome (Boute et al., 2000). The gene, identified by positional cloning, encodes a novel integral membrane protein known as podocin that is almost exclusively expressed in the podocytes of kidney glomeruli.

Lipodystrophy (OMIM #151660). Missense mutations in the gene encoding lamin A/C (LMNA) were identified in patients with autosomal dominant disorder familial partial lipodystrophy (FPLD), which maps to 1q21-q23 (Speckman et al., 2000). Similar findings were reported by Shackleton and colleagues where five different missense mutations were found in ten FPLD families and three isolated cases of PLD (Shackleton et al., 2000). Mutations in this gene were also found in families with Emery-Dreifuss muscular dystrophy (Bonne et al., 1999). Shackleton and colleagues suggested that site-specific amino acid substitutions lead to varied function of the lamin A/C protein in different cell types.

The PEA15 gene (OMIM #603434) was examined as a 1q21 type 2 diabetes candidate gene, and single nucleotide polymorphisms in this gene were shown to be in allelic association in a set of Pima Indians with type 2 diabetes (Wolford et al., 2000). However, Wolford and colleagues concluded that mutations in PEA15 most likely do not contribute to type 2 diabetes susceptibility.