Abirami Chidambaram

Mutations of the Human Homolog of Drosophila patched in the Nevoid Basal Cell Carcinoma Syndrome

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. NBCCS maps to chromosome 9q22.3. Familial and sporadic BCCs display loss of heterozygosity in this region, consistent with the gene being a tumor suppressor. A human sequence (PTC) with strong homology to the Drosophila segment polarity gene, patched, was isolated from a YAC and cosmid contig of the NBCCS region. Mutation analysis revealed alterations of PTC in NBCCS patients and in related tumors. We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types.

A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy

Stargardt disease (STGD, also known as fundus flavimaculatus; FFM) is an autosomal recessive retinal disorder characterized by a juvenile-onset macular dystrophy, alterations of the peripheral retina, and subretinal deposition of lipofuscin-like material. A gene encoding an ATP-binding cassette (ABC) transporter was mapped to the 2-cM (centiMorgan) interval at 1p13-p21 previously shown by linkage analysis to harbour the STGD gene. This gene, ABCR, is expressed exclusively and at high levels in the retina, in rod but not cone photoreceptors, as detected by in situ hybridization. Mutational analysis of ABCR in STGD families revealed a total of 19 different mutations including homozygous mutations in two families with consanguineous parentage. These data indicate that ABCR is the causal gene of STGD/FFM.

A Mammalian patched Homolog Is Expressed in Target Tissues of sonic hedgehog and Maps to a Region Associated with Developmental Abnormalities

Drosophila patched is a segment polarity gene required for the correct patterning of larval segments and imaginal discs during fly development and has a close functional relationship with hedgehog. We have isolated a complete human PATCHED cDNA sequence, which encodes a putative protein of 1296 amino acids, and displays 39% identity and 60% similarity to the Drosophila PATCHED protein. Hydropathy analysis suggests that human PATCHED is an integral membrane protein with a pattern of hydrophobic and hydrophilic stretches nearly identical to that of Drosophila patched. In the developing mouse embryo, patched is initially detected within the ventral neural tube and later in the somites and limb buds. Expression in the limb buds is restricted to the posterior ectoderm surrounding the zone of polarizing activity. The results show that patched is expressed in target tissues of sonic hedgehog, a murine homolog of Drosophila hedgehog suggesting that patched/hedgehog interactions have been conserved during evolution. Human PATCHED maps to human chromosome 9q22.3, the candidate region for the nevoid basal cell carcinoma syndrome. Patched expression is compatible with the congenital defects observed in the nevoid basal cell carcinoma syndrome.

Characterization of a human homolog (OVOL1) of the Drosophila ovo gene, which maps to chromosome 11q13.

loci map to different chromosomes. In addition to islet cells, these proteins are expressed in other neuroendocrine cells and in brain, and IA-2 expression has been shown to be upregulated in fibroblasts after mitogenic stimulation [11]. Another receptor-type PTP with demonstrated phosphatase activity, Ptprc (CD45), maps at 74 cM on mouse Chr 1, a site considerably distal to the region containing Ptprn. In segregation analysis between the autoimmune IDDM-prone NOD strain and diabetes-resistant C57BL/10 mice, a diabetes susceptibility locus (Idd5) has been reported to map to the a region of Chr 1 near Ptprn [12]. Mouse Genome Database (MGD) currently shows the Idd5 locus at 40 cM, but this is arbitrary, since multiple subphenotypes associated with IDDM in NOD mice map to various regions of Chr 1. The present data would position Ptprn between Cryg (32 cM in MGD) and Tns (44.5 cM in MGD), thus making Ptprn a potential candidate gene for Idd5. No Idd gene has yet been observed in segregation on the most distal end of mouse Chr 12, where the Ptprn2 locus resides. Unlike humans, NOD mice do not produce precipitating antibodies to the IA-2 protein [13], pointing to differences in autoimmune responsiveness of mice versus humans to islet autoantigens.

Genetics of the nevoid basal cell carcinoma syndrome.

Publisher Summary This chapter focuses on the genetics of the nevoid basal cell carcinoma syndrome. The nevoid basal cell carcinoma syndrome (NBCCS), also known as “Gorlin syndrome,” is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), odontogenic kerarocysts, pits of the palms and soles, and a spectrum of skeletal and developmental abnormalities. It is a complex hamartoneoplastic-malformation syndrome with over 100 signs and symptoms primarily involving the skin, central nervous system, and skeletal system. One of the most striking and consistent features of this syndrome is the number and distribution of BCCs in NBCCS patients in contrast to that observed in the general population. The phenotypic manifestation and spectrum of associated defects also provide valuable clues as to possible candidate loci that may be involved in the syndrome. The clinical features of NBCCS and the wide phenotypic spectrum of these features indicate that the gene for this syndrome must be involved in the normal course of embryogenesis and in addition be involved in cellular regulatory processes, such as cell division and differentiation. Malformations involving the skeletal and nervous system and facial dysmorphology indicate that defects in this gene affect early embryonic processes. The spectrum of developmental anomalies associated with the mes mutation makes it an interesting candidate for a mouse model for NBCCS.

Characterization of a YAC contig containing the NBCCS locus and a novel Kruppel-type zinc finger sequence on chromosome segment 9q22.3.

Gorlins syndrome or nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by a familial or hereditary predisposition to basal cell carcinomas (generally multiple and of early onset), odontogenic keratocysts (jaw cysts), palmar and plantar pits, a wide variety of developmental defects, as well as cancers such as medulloblastomas and ovarian fibromas. The gene for NBCCS has been mapped to human chromosome region 9q22.1–q31 by linkage analysis and by cytogenetic evidence of deletions in this region in patients with the syndrome. This is supported by loss of heterozygosity in tumors of polymorphic marker loci flanked by D9S197 and D9S180. We have utilized sequence tagged site (STS) mapping and somatic cell hybrid panel analysis to construct two overlapping yeast artificial chromosome (YAC) contigs spanning this region of the genome. We used the YAC contigs to identify a new zinc finger gene containing a highly informative microsatellite locus. Genes Chromosom. Cancer 18:212–218, 1997.

Pulsed-field gel electrophoresis and FISH mapping of chromosome 9q22: placement of a novel zinc finger gene within the NBCCS and ESS1 region

Chromosome 9q22 is a gene-rich region to which several human disease loci have been mapped. Pulsed field gel electrophoresis (PFGE) and FISH were used to determine the order of and distance between 12 chromosome 9q22 markers flanked by D9S196 and D9S180. D9S780 and XPA were within 190 kb of each other and hybridized to the same 460-kb NotI fragment as D9S180. ZNF169, a novel kruppel-type gene, and D9S280 shared several PFGE fragments indicating that they are not more than 300 kb apart. Interphase FISH showed that COL15A1 lies distal to the region bounded by D9S180 and D9S196 and that ZNF169 is adjacent to D9S196. Based on the restriction fragment lengths in this region and estimates from FISH, the distance from D9S180 to D9S196 is not less than 2 Mb.