Aromatase deficiency in a tall man: Case report of two novel mutations and review of literature.

Aromatase (CYP19A1) is the only enzyme known to catalyse the conversion of androgen to estrogen. Aromatase deficiency occurs due to mutation in CYP19A1gene which has an autosomal recessive inheritance pattern. It leads to decrease in estrogen synthesis and delayed epiphyseal closure, eunuchoid habitus and osteopenia. We are presenting here, a 24 years old male, with history of progressive increase in height and knock knees. X-ray showed open wrist and knee epiphysis. The serum testosterone level was normal and serum estradiol level was undetectable. Semen analysis showed azoospermia. Clinical exome sequencing gave two novel mutations in CYP19A1. The first variant was a novel single nucleotide deletion of thiamine at 570th base of the cDNA (c.570delT) of CYP19A1 gene. The second variant detected was again a novel one in the same gene in Exon 5 corresponding 344th base of the cDNA (c344G>A) resulting in a missense mutation of 115th arginine to glutamine in the protein. Sanger sequencing showed that the later mutation was inherited from the father. The patient was started on oral estradiol valerate for epiphyseal closure to prevent further increase in height. Only 15 mutations have been reported in the aromatase gene in males till date, our report of these novel mutations will be an add-on to the literature.

Low Levels of Prohibitin in Substantia Nigra Makes Dopaminergic Neurons Vulnerable in Parkinson's Disease.

Since substantia nigra (SN) and ventral tegmental area (VTA) dopaminergic neurons are, respectively, susceptible or largely unaffected in Parkinson's disease (PD), we searched for protein(s) that regulates this differential sensitivity. Differentially, expressed proteins in SN and VTA were investigated employing two-directional gel electrophoresis- matrix-assisted laser desorption ionization time of flight (MALDI-TOF-TOF) analyses. Prohibitin, which is involved in mitochondrial integrity, was validated using immunoblot, qRT-PCR, and immunohistochemistry in normal mice as well as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-model, PD postmortem human brains, and PD cybrids. In prohibitin over-expression, differentiated SH-SY5Y neurons were investigated for their susceptibility to PD neurotoxin, 1-methyl-4-phenyl-pyridnium (MPP+). Prohibitin, Hsc73, and Cu-Zn superoxide dismutase (Cu-Zn SOD) were highly expressed in VTA, whereas heat shock protein A8 (HSPA8) and 14-3-3ζ/δ were 2-fold more in SN. Prohibitin level was transiently increased in SN but unaltered in VTA on the third day of MPTP-induced mice, whereas in PD human brains, prohibitin was depleted in both these regions. Parallel to mouse SN, an enhanced prohibitin expression was found in human PD cybrids. In MPP+-induced cellular model of PD, reduction in prohibitin level was found to be associated with a loss in its binding with Ndufs3, a mitochondrial complex I protein partner. Prohibitin over-expression resisted MPP+-induced neuronal death by restoring mitochondrial membrane potential, preventing reactive oxygen species generation and cytochrome c release into cytosol. These protective phenomena exerted by prohibitin over-expression altogether hinder caspase 3 activation induced by MPP+. These results imply that prohibitin is an important negotiator protein that regulates dopaminergic cell death in SN and their protection in VTA in PD.

Does serotonin deficit mediate susceptibility to ADHD?

The onset of attention-deficit-hyperactivity-disorder (ADHD) in childhood is characterized by developmentally inappropriate levels of hyperactivity, impulsivity and inattention. A chronic deficit of serotonin (5-HT) at the synapse may trigger symptoms of ADHD. This review focuses on neuro-anatomical, experimental and clinical pharmacological evidence, as well as the genetic underpinnings of serotoninergic involvement in the etiology of ADHD. Neuro-anatomical investigations suggest that serotonin through the orbitofrontal-striatal circuitry may regulate behavioral domains of hyperactivity and impulsivity in ADHD. Studies from animal models of ADHD indicate intimate interplay between 5-HT and dopaminergic neurotransmission. Selective serotonin re-uptake inhibitors, as also non-stimulant drugs acting on the 5-HT system are, however, clinically effective. They impart less severe side effects in patients with no risk of addiction. Oral administration of l-tryptophan, the amino acid precursor of 5-HT, significantly alleviates ADHD symptoms. Given the multifactorial nature of ADHD, candidate gene and genome-wide association studies have suggested that serotoninergic gene variants are associated with increased risk of ADHD with each locus individually exerting a modest effect on overall risk.

No causal role for the G482T and G689T polymorphisms in translation regulation of serotonin transporter (SLC6A4) or association with attention-deficit-hyperactivity disorder (ADHD).

PURPOSE OF THE STUDY: The G482T and G689T polymorphisms in the 3'-UTR of serotonin transporter (SLC6A4) are implicated in translational regulation and allelic variants may mediate susceptibility to attention-deficit-hyperactivity disorder (ADHD). Accordingly, we examined influence of allelic variation on stable secondary structure formation and on seed sequences necessary for microRNA-binding. Furthermore, 90 ADHD cases from India were genotyped for these markers and tested for association with ADHD. METHODS: The Mfold software was used for secondary structure predictions and miRNA-binding sequences were obtained from the PicTar database. Using a family-based study design we assessed genetic association by means of the haplotype-based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) statistics. With respect to G689T, previously published TDT data were included in pooled analysis. RESULT: Secondary structure analysis reveals that G482, U482, G689 and U689 conformers are energetically similar. Unlike G482, the U482 change maps within a loop and this conformer differs in free energy by approximately 4.4kcal/mol. While G482T is proximal to various miRNA-binding sequences, it is not part of the seed sequence for any of them. Thus, G482T and G689T polymorphisms do not regulate SLC6A4 translation in cis. From the HHRR (chi(2)=0.860, p=0.353; R.R.=1.11; 95% C.I.=0.89-1.65 for G482T; chi(2)=0.902, p=0.342; R.R.=1.17; 95% C.I.=0.83-1.32 for G689T), TDT (chi(2)=1.33, p=0.25; O.R.=1.35; 95% C.I.=0.94-1.94 for G482T; chi(2)=1.45, p=0.23; O.R.=1.44; 95% C.I.=0.94-2.22 for G689T) and pooled TDT (chi(2)=0.52, p=0.47; O.R.=1.05; 95% C.I.=0.96-1.15) statistics we infer that these polymorphisms are not associated with risk of ADHD.

A family-based study of Indian subjects from Kolkata reveals allelic association of the serotonin transporter intron-2 (STin2) polymorphism and attention-deficit-hyperactivity disorder (ADHD).

Serotonin transporter (SLC6A4) polymorphisms are variously implicated in mediating susceptibility to attention-deficit-hyperactivity disorder (ADHD), a highly heritable and heterogeneous disorder with onset in childhood. Since there has been no survey in this regard from India, a sample of 56 ADHD cases and 174 healthy individuals from Kolkata were genotyped for the SLC6A4 promoter (5-HTTLPR) and intron-2 (STin2) polymorphisms. We report that the observed distribution of allele frequencies is consonant with that expected as per Hardy-Weinberg equilibrium proportions. Pair-wise combination of alleles comprising the 5-HTTLPR and STin2 polymorphic systems exhibit significant (chi(2) = 14.74, df = 1; P = 0.0001) linkage disequilibrium of low magnitude (D' = 0.269). The estimates of haplotype-based haplotype relative risk (HHRR) (chi(2) = 4.92, P = 0.027; RR = 1.47; 95% CI = 1.01-2.13) and transmission disequilibrium test (TDT) statistics (chi(2) = 7.00, P = 0.008; OR = 3.00; 95% CI = 1.53-5.90) using a family-based study design, indicate significant preferential transmission of the STin2.12 (A12) allele to ADHD cases. Maternal inheritance of the A12 allele is significant in terms of the HHRR (chi(2) = 6.53, P = 0.011; RR = 2.00; 95% CI = 1.08-3.72) and TDT (chi(2) = 8.07, P = 0.005; OR = 6.50; 95% CI = 1.76-23.98) suggesting a novel role for epigenetic mechanisms in the etiology of ADHD. Similar analyses yielded no evidence of association between the 5-HTTLPR polymorphism and ADHD. Studies including additional polymorphic markers, ADHD subjects and other ethnic groups are warranted to further substantiate the present findings.