Is Sos A Contiguous Gene Syndrome

There are at least 22 genes that map within the common deleted region (UCSC Genome Browser, May 2004 Assembly, http://genome.ucsc.edu/cgi-bin/hgGateway) (Fig. 2). Both SoS-REPs contain two genes, THOC3 and NY-REN-7 (Fig. 2). THOC3 and NY-REN-7 have open reading frames that are completely conserved in SoS-PREP and SoS-DREP. The PROP1 gene maps only to SoS-DREP between subunit E and C' (Fig. 2A). Among those 22 genes deleted, NSD1, the plasma coagulation factor 12 gene (F12, OMIM +234000), the prophet of the PIT-1 gene (PROP1, OMIM +601538), and the xylosylprotein P 1,4-galactosyltransferase, polypeptide 7 gene (B4GALT7, also known as xylosylprotein 4-P-galactosyltransferase I gene, XGTP1, OMIM *604327) may be directly related to human phenotypes.

F12 encodes the coagulation factor XII, also known as Hageman factor. Heterozygous deletion of F12 may result in partial F12 deficiency, which could present with a slight to moderate bleeding tendency (44,45). Low levels of factor XII activity may also be a risk factor for repeated spontaneous abortions or skin ulcers (46,47). A common polymorphism in the 5'-untranslated region of F12, the c.46C > T substitution, was found to be associated with low F12 level (48). In cases of c.46T/T, the value of F12 was remarkably decreased. Soria et al. (49) reported that the 5q33-qter region is a quantitative risk factor for thrombosis using genome wide linkage analysis. A novel homozygous p.W484C mutation was shown to induce low F12 levels (50). It is important to evaluate F12 in SoS patients with MDs, although such a risk has not been known in SoS.

Homozygous or compound-heterozygous defects of PROP1 result in combined pituitary hormone deficiency including GH, PRL, TSH, LH and FSH (OMIM +601538) (51). So far,

Fig. 2. (A) Physical map depicting microdeletions found in Sotos syndrome (SoS) and two low-copy repeat sequences, termed proximal-repeat (SoS-PREP) and distal-repeat (SoS-DREP) at 5q35. The Sos-REPs, indicated as black boxes, are proximal and distal to NSD1. Among 22 genes that map within the deletion interval, NSD1, the SoS-REP-specific predicted genes (THO3, NY-REN-7, and PROP1), and possible human phenotype-related genes (F12, GPRK6, B4GAL4T7) are presented. THOC3 and NY-REN-7 map to both SoS-PREP and SoS-DREP. Bold bi-directional arrow represents a deleted region. An approx 2-Mb microdeletion is the most commonly observed in SoS. (B) There are six subunits of more than 96% sequence identity between the proximal and the distal SoS-REPs (A—F); their orientation is depicted as arrow. All subunits except C' are inverted with respect to each other. Dotted lines indicate unique sequence in low-copy repeats. Three relevant genes are shown.

Fig. 2. (A) Physical map depicting microdeletions found in Sotos syndrome (SoS) and two low-copy repeat sequences, termed proximal-repeat (SoS-PREP) and distal-repeat (SoS-DREP) at 5q35. The Sos-REPs, indicated as black boxes, are proximal and distal to NSD1. Among 22 genes that map within the deletion interval, NSD1, the SoS-REP-specific predicted genes (THO3, NY-REN-7, and PROP1), and possible human phenotype-related genes (F12, GPRK6, B4GAL4T7) are presented. THOC3 and NY-REN-7 map to both SoS-PREP and SoS-DREP. Bold bi-directional arrow represents a deleted region. An approx 2-Mb microdeletion is the most commonly observed in SoS. (B) There are six subunits of more than 96% sequence identity between the proximal and the distal SoS-REPs (A—F); their orientation is depicted as arrow. All subunits except C' are inverted with respect to each other. Dotted lines indicate unique sequence in low-copy repeats. Three relevant genes are shown.

three SoS cases associated with hypothyearsoidism have been reported (52,53). Unmasking of the recessive allele is possible when one allele harbors a PM and the other is deleted. It may be worth investigating PROP1 if hypothyearsoidism is observed.

B4GALT7 regulates the synthesis of various glycosaminoglycans (GAGs). GAGs are basic components of heparin/heparan sulfate or those of chondroitin sulfate/dermatan sul-

fate and have an important role in the formation of various tissues and organs (54). Defects of GAGs may be possibly responsible for the various forms of so-called mucopolysaccharidoses. In the progeroid type of Ehlers-Danlos syndrome, compound heterozygosity for p.A186D and p.L206P mutations of B4GALT7 was confirmed. The father was heterozygous for the p.L206P allele and mother heterozygous for the p.A186D allele (55,56). Although only one case with such mutations has been reported, carrier status for such PMs in contributions with hemizygous deletion of B4GALT7 in SoS patients with MDs could contribute to phenotypic variability.

GPRK6 encodes G protein-coupled receptor kinase 6 protein (GPRK6) (OMIM *600869), which can regulate G protein-coupled receptors. Using immunohistochemistry, GPRK6 expression was confirmed in striatal neurons receiving dopaminergic input and postsynaptic D2/D3 dopamine receptors were targets of GPRK6 (57). Investigation of GPRK6 by gene targeting to create a knockout animal shows higher sensitivity to psychostimulants including cocaine and amphetamine especially in homozygous mice rather than heterozygous, suggesting that such high sensitivity may be related to some potential psychiatric diseases in human (58). It would be interesting to evaluate for different psychiatric and behavioral aspects between SoS cases with MD versus PM.

The influence of the deletion of 21 genes other than NSD1 needs to be carefully evaluated, as some genes may affect the severity of phenotypes in MD patients.

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