NucleaRDB: Extraction of mutation data from the literature

This data was extracted from Medline abstracts and full texts (when available) in an automated manner.

The table below describes the selected point mutation and provides links to other documents. The sentence(s) where the point mutation P12A was found are listed after the table.

The mutated residues are also indicated in the family sequence alignments and hyperlinked to the corresponding mutation pages.

Point mutation P12A in PPAT_HUMAN

Relevant sentences:

P12A

• Intervention(s): Assay for P12A and P115Q variants and measure BMI

• Result(s): Fourteen subjects were heterozygous for P12A ; two were homozygous

• Thirty-nine subjects had BMI values at two time points ; mean BMI was significantly greater in the P12A carriers at time point 2

• Those P12A carriers obese at time point 1 became more obese ; lean mutation carriers tended to remain lean

• Annual rate of increase in BMI was significantly greater in the P12A carriers than the noncarriers

• Conclusion(s): Our findings suggest that P12A may be a genetic marker indicating risk for obesity persisting into adolescence

• Future studies are needed to determine whether the divergent effects of P12A persist into adulthood , to elucidate the mechanism of this effect , and to replicate our findings in other populations

• Author Keywords: Body mass index ; premature pubarche ; hyperandrogenism ; obesity ; PPAR ; polycystic ovary syndrome Article Outline Materials and methods Subjects Hormone studies Genetic analysis Statistical analysis Results Subjects Genotype analysis Is P12A associated with increased BMI? Is P12A associated with increased rate of change in BMI? Discussion The peroxisome proliferator-activated receptor-small gamma , Greek (PPAR-small gamma , Greek) is a nuclear ligand-dependent transcription factor that promotes adipocyte differentiation and influences insulin sensitivity [1 and 2 ]

• One change , C rightwards arrow G at nucleotide 34 , predicts the substitution of proline by alanine at codon 12 (P12A) , a nonconservative missense mutation

• Allele frequency for the P12A variant is reported to range from 0.01 in Chinese to 0.12 in whites [8 ]

• Functional analysis demonstrated that the P12A variant has lower transactivation activity than the P12 variant [9 and 10 ]

• In some studies , P12A has been associated with obesity or diabetes [11 , 12 and 13 ]

• In other populations , the P12A allele appears to be associated with a modest decrease in the risk for diabetes [14 and 15 ]

• Among obese white women , the P12A variant appeared to be protective against diabetes , but was associated with early age of onset of obesity [16 ]

• Divergent effects on body mass index (BMI) were observed among Danish adult men where , in a 25-year follow-up , the rate of increase in BMI (capital Delta , GreekBMI / yr) was greater among obese homozygous P12A carriers than the capital Delta , GreekBMI / yr among lean homozygous P12A carriers [17 ]

• To ascertain whether either of these genetic variants , P12A or P115Q , plays a role in the development of obesity in childhood and adolescence , we determined the BMI in 98 children with premature pubarche and adolescent girls with hyperandrogenism

• For P12A , the polymerase chain reaction (PCR) primers , sense (5'-GCCAATTCAAGCCCAGTC-3') and anti-sense (5'-GATATGTTTGCAGACAGTGTATCAGTGAAGGAATCGCTTTCCG-3') , generated a 270-bp product

• A BstUI site is introduced in the presence of the C rightwards arrow G change at nucleotide 34 predicted to generate the P12A missense mutation

• After BstUI digestion at 60°C for 2 hours and electrophoresis using a 2.5% agarose gel , expected sizes are 270 bp for the wild-type (P12) allele ; 270 , 227 , and 43 bp for heterozygotes ; and 227 and 43 bp for P12A homozygotes [8 ]

• Genotype analysis Of the 45 girls in group 1 , 34 were homozygous for the wild-type allele , 10 were heterozygous for P12 A , and one was homozygous for P12A

• Frequency of the P12A allele was 13.3%

• For group 2 , 17 children were homozygous for the wild-type allele and one girl was heterozygous for P12A

• Frequency of P12A was 3.1% for group 2

• For group 3 , 31 girls were homozygous for the wild-type allele , three were heterozygous , and one was homozygous for P12A

• Frequency of the P12A allele was 7.1% in group 3

• Overall allele frequency for P12A in our 98 patients was 9% , which compares well with the reported frequency of 12% in whites [8 ]

• Is P12A associated with increased BMI? Our hypothesis is that PPAR affects development of obesity by increasing the rate of increase in BMI over time in carriers of the P12A mutant allele

• For group 1 , children <8 years , the mean BMI was 18.8 ± 3.2 kg / m2 for the 34 subjects homozygous for the P12 allele: P12A noncarriers

• For the purpose of this correlation , the single subject homozygous for the P12A allele was included with the heterozygous subjects: P12A carriers

• There were no significant differences in BMI , mean basal androstenedione concentrations , or SHBG concentrations between P12A carriers and noncarriers

• All the boys in group 2 were P12A noncarriers

• Only one girl in group 2 was a P12A carrier ; her BMI was 27.8 kg / m2 at age 8.4 years

• The mean BMI was 24.1 ± 6.2 kg / m2 for the remaining 10 girls who were P12A noncarriers

• For group 3 , mean BMI was 30.7 ± 7.5 kg / m2 for the 31 P12A noncarriers

• Again , the single subject homozygous for the P12A allele was included with the three heterozygous subjects

• Mean BMI for these four P12A carriers was 35.7 ± 5.5 kg / m2 (range , 29.1– ; 42.0 kg / m2)

• All four subjects who carried the P12A variant were obese

• Mean basal androstenedione concentrations did not differ significantly between the subjects homozygous for the P12 allele and the P12A carriers

• The SHBG concentrations were available for only two of the P12A carriers , both had values of 0.4 small mu , Greekg / dL

• Is P12A associated with increased rate of change in BMI? For 39 subjects , BMI values at two time points at least 2 years apart were available

• Of these 39 subjects , there were 28 girls homozygous for P12 (P12A noncarriers) , 10 girls heterozygous for P12A , and one girl homozygous for P12A

• As there was only a single homozygous subject , she was included with the heterozygous subjects as a P12A carrier for the analyses

• Mean chronologic ages did not differ significantly between P12A noncarriers and the P12A carriers at either time point (Table 2 )

• For the 39 subjects , mean BMI at time point 1 did not differ between the P12A noncarriers and P12A carriers

• At time point 2 , mean BMI was significantly greater among the P12A carriers than the noncarriers , P = .029 (Table 2 )

• Characteristics of the 39 subjects (mean ± SD) for whom two time points were available.legend , legend View Table (7K) Because mean BMI was greater among P12A carriers at time point 2 , the subjects were classified as to whether their initial BMI was greater or less than the 85th percentile expected for their chronologic age [29 ] to determine whether BMI status at time point 1 influenced BMI status at time point 2

• Seventeen (61%) of 28 P12A noncarriers and 7 (63.6%) of 11 P12A carriers had BMI values greater than the 85th percentile expected for their chronologic age at time point 1

• Mean BMI at time point 1 did not differ significantly between obese P12A carriers and noncarriers

• Furthermore , when BMI values were expressed as the difference from predicted 85th percentile for BMI for chronologic age at time point 1 to standardize for age , there was no significant difference in mean BMI between obese P12A carriers and noncarriers (Table 3 ) , P = .20

• Characteristics of the 39 subjects (mean ± SD) for whom two time points were available , classified by whether they were initially obese or nonobese.legend , legend View Table (8K) At time point 2 , 17 P12A noncarriers (15 of the original 17) and nine P12A carriers (including the original 7) had BMI values greater than the 85th percentile for their age

• Of the four girls with BMI values greater than 40 kg / m2 , three were heterozygous for P12A

• Mean BMI at time point 2 was significantly greater in the seven initially obese P12A carriers compared to obese noncarriers , P = .029 (Table 3 ) , as were BMI values expressed as the difference from predicted 85th percentile for BMI for chronologic age at time point 2 , P = .018

• Of the four P12A carriers with BMI values less than the 85th percentile at time point 1 , three had BMI values less than 23 kg / m2 at the second time point

• For one heterozygous carrier of P12A , her initial BMI was 16.5 kg / m2 and most recent BMI , 12.5 years later , was 42.8 kg / m2

• Mean BMI at time point 2 was not significantly different in the four initially nonobese P12A carriers , P = .20 (Table 3 )

• The rate of increase in BMI per year (capital Delta , GreekBMI / yr) for the 39 subjects was significantly greater in the P12A carriers than the noncarriers , 1.7 ± 0.7 vs

• The original results reported for adults suggested that P12A carriers who were initially obese showed a higher rate of increase in BMI than noncarriers [17 ]

• The parameter estimates from the generalized linear model showed that the effect of being a P12A carrier of increasing capital Delta , GreekBMI / yr , escalated with greater BMI at time point 1

• Among our subjects , there were no significant differences in BMI values between P12A carriers and noncarriers in any of the three groups

• Three of the four lean (<85% BMI for age) P12A carriers remained lean , whereas the obese P12A carriers showed both significantly greater mean BMI and greater mean gain in BMI per year

• Thus , P12A may protect lean individuals from obesity while predisposing obese individuals to greater weight gain

• Of interest , in a 25-year follow-up study of Danes , obese homozygous P12A carriers showed higher BMI and greater capital Delta , GreekBMI / yr (0.27 ± 0.24 kg / m2 / yr) than P12A noncarriers [17 ]

• Nonobese homozygous P12A carriers showed a lower capital Delta , GreekBMI / yr (0.11 ± 0.11 kg / m2 / yr) compared to nonobese P12A noncarriers [17 ]

• Similar to our findings , the P12A variant in the presence of preexisting obesity was associated with increased weight gain , whereas lean individuals appeared to be protected from obesity [17 ]

• The difference between our findings in children and those reported among the Danish men is that our subjects were heterozygous for P12A , whereas the BMI increase was greater only in obese Danish men homozygous for P12A

• An alternative explanation is that the effect of the P12A variant is influenced by the ratio of dietary polyunsaturated fat to saturated fat in that P12A carriers show greater BMI when the dietary polyunsaturated fat to saturated fat ratio is low [39 ]

• Among women of Canadian Oji-Cree descent , P12A was associated with type 2 diabetes mellitus [42 ]

• Similar to lean humans carrying P12A , mice heterozygous for null mutations show greater insulin sensitivity without any significant difference in body weight compared to wild-type animals [44 and 45 ]

• Herein , we report that the P12A variant of PPAR-small gamma , Greek2 in obese children with premature pubarche is associated with an increased risk for obesity during adolescence independent of risk due to preexisting obesity

• Our findings suggest that P12A may be a genetic marker indicating risk for obesity persisting into adulthood

• Future studies are necessary to determine whether the divergent effects of P12A persist into adulthood , to elucidate the mechanisms of this effect , and to replicate our findings in other populations

F.Horn (nucleardbcmbi.kun.nl), 21-Apr-2005