Showing papers by "Simon G. Gregory published in 2000"

LMNA, encoding lamin A/C, is mutated in partial lipodystrophy.

Abstract: The lipodystrophies are a group of disorders characterized by the absence or reduction of subcutaneous adipose tissue. Partial lipodystrophy (PLD; MIM 151660) is an inherited condition in which a regional (trunk and limbs) loss of fat occurs during the peri-pubertal phase. Additionally, variable degrees of resistance to insulin action, together with a hyperlipidaemic state, may occur and simulate the metabolic features commonly associated with predisposition to atherosclerotic disease. The PLD locus has been mapped to chromosome 1q with no evidence of genetic heterogeneity. We, and others, have refined the location to a 5.3-cM interval between markers D1S305 and D1S1600 (refs 5, 6). Through a positional cloning approach we have identified five different missense mutations in LMNA among ten kindreds and three individuals with PLD. The protein product of LMNA is lamin A/C, which is a component of the nuclear envelope. Heterozygous mutations in LMNA have recently been identified in kindreds with the variant form of muscular dystrophy (MD) known as autosomal dominant Emery-Dreifuss MD (EDMD-AD; ref. 7) and dilated cardiomyopathy and conduction-system disease (CMD1A). As LMNA is ubiquitously expressed, the finding of site-specific amino acid substitutions in PLD, EDMD-AD and CMD1A reveals distinct functional domains of the lamin A/C protein required for the maintenance and integrity of different cell types.

A Preliminary Gene Map for the Van der Woude Syndrome Critical Region Derived from 900 kb of Genomic Sequence at 1q32–q41

Abstract: There are >300 described syndromes that have cleft lip and palate as an associated characteristic (OMIM, http://www.ncbi.nlm.nih.gov/Omim/). Van der Woude syndrome (VWS) is the most common form of syndromic cleft lip and palate and accounts for ∼2% of all cleft lip and palate cases (OMIM no. 119300). VWS has been recognized for more than a century (Murray 1860) and was assigned its eponym following Anne Van der Woude's description of the disorder in 1954. Distinguishing characteristics include cleft lip with or without cleft palate, isolated cleft palate, bilateral lip pits, hypodontia, normal intelligence, and an autosomal-dominant mode of transmission with a high degree of penetrance (Burdick et al. 1985). VWS is distinguished from nonsyndromic cleft lip and palate by the presence of lower lip pits, which are found in most affected individuals with the disorder (Janku et al. 1980; Shprintzen et al. 1980; Burdick et al. 1985). The unusual lip pits seen in VWS are believed to be an embryonic remnant from an early stage of development (Onofre et al. 1997), and are rarely seen in other settings. There are no other systemic, cognitive, or craniofacial anomalies to differentiate VWS from nonsyndromic forms of clefting. Isolated clefts of the palate (CPO; secondary palate defects) are genetically and embryologically distinct from clefts that include the lip or the lip and palate together (CL/P; primary palate defects; Fraser 1955). VWS is the only single-gene form of clefting in which affected individuals within the same family commonly have either isolated cleft palate only or clefts of the lip and palate. This unique feature suggests that VWS may arise from an abnormality in a gene that disrupts a very early stage of palate development when a common factor is involved in the formation of both the primary and secondary palates. Positional cloning of the VWS gene has progressed through genetic and physical mapping. Initially, the locus for VWS was suggested through the reporting of a patient with a large cytogenetic anomaly at 1q32–q41 by Bocian and Walker (1987) and by a suggestion of linkage to the Duffy blood group by Wienker et al. (1987). Murray et al. (1990) confirmed linkage of Van der Woude syndrome to 1q32, and subsequently, two microdeletions (Sander et al. 1994; Schutte et al. 1999) as well as individual recombinants (Schutte et al. 1996) further narrowed the region to a 1.6-cM region between the flanking markers D1S491 and D1S205. The identification of deletion mutations in three independent cases of VWS (Bocian and Walker 1987; Sander et al. 1994; Schutte et al. 1999), suggest that VWS is caused by haploinsufficiency of a gene at the VWS locus (Schutte et al. 1999). Haploinsufficiency is a common theme in autosomal-dominant clefting syndromes that include Waardenburg syndrome (OMIM no. 193500), Basal Cell Nevus syndrome (OMIM no. 109400), Rieger syndrome (OMIM no. 180500), Treacher Collins syndrome (OMIM no. 154500), and Stickler syndrome (OMIM no. 108300, 184840). In these syndromes, haploinsufficiency is evidenced by deletions and/or loss-of-function mutations (Lu-Kuo et al. 1993; Wu et al. 1993; Semina et al. 1996; Edwards et al. 1997; Wicking et al. 1997; DeStefano et al. 1998; Snead and Yates 1999). Thus, from a VWS mutation search, we expect to find a range of loss-of-function mutations in one of the positional candidates in addition to the three previously identified deletions. The autosomal-dominant clefting syndromes described above also suggest the types of genes that would make ideal candidates for the VWS locus. Those genes encode for either transcription factors (Tassabehji et al. 1992; Semina et al. 1996), extracellular matrix proteins (Ahmad et al. 1991) or proteins involved in signal transduction (Johnson et al. 1996). Additional candidate functions for the VWS gene can be deduced from transgenic mice whose phenotype includes an orofacial cleft. To date, ∼30 knockout strains of mice exhibit some form of orofacial clefts (http://tbase.jax.org), and the product of those genes includegrowth factors in addition to transcription and signaling factors (for review, see Schutte and Murray 1999). Although genes with these functions are excellent candidates for the VWS locus, we note that not every gene involved in an autosomal-dominant clefting syndrome has such obvious developmental functions (Dixon et al. 1997). To identify the gene responsible for VWS, we constructed a contig of bacterial clones that spans the VWS locus. STS content analysis and large-scale sequencing of this entire contig resulted in the identification of 4 known genes, 11 novel genes, 9 putative genes, and 3 psuedogenes in the 1.1-Mb region surrounding the 350-kb VWS critical region. In addition, mutation analysis excluded several positional candidates for the VWS locus.