Koumudi Godbole

Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

Heterozygous coding mutations in the INS gene that encodes preproinsulin were recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal folding of proinsulin, which leads to beta-cell death through endoplasmic reticulum stress and apoptosis. We now report 10 different recessive INS mutations in 15 probands with neonatal diabetes. Functional studies showed that recessive mutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylation signal. A subset of recessive mutations caused abnormal INS transcription, including the deletion of the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-cell defect, patients with recessive INS mutations had a lower birth weight (−3.2 SD score vs. −2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant INS mutations. Mutations in the insulin gene can therefore result in neonatal diabetes as a result of two contrasting pathogenic mechanisms. Moreover, the recessively inherited mutations provide a genetic demonstration of the essential role of multiple sequence elements that regulate the biosynthesis of insulin in man.

An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy

DNA polymerase δ, whose catalytic subunit is encoded by POLD1, is responsible for lagging-strand DNA synthesis during DNA replication. It carries out this synthesis with high fidelity owing to its intrinsic 3′- to 5′-exonuclease activity, which confers proofreading ability. Missense mutations affecting the exonuclease domain of POLD1 have recently been shown to predispose to colorectal and endometrial cancers. Here we report a recurring heterozygous single-codon deletion in POLD1 affecting the polymerase active site that abolishes DNA polymerase activity but only mildly impairs 3′- to 5′-exonuclease activity. This mutation causes a distinct multisystem disorder that includes subcutaneous lipodystrophy, deafness, mandibular hypoplasia and hypogonadism in males. This discovery suggests that perturbing the function of the ubiquitously expressed POLD1 polymerase has unexpectedly tissue-specific effects in humans and argues for an important role for POLD1 function in adipose tissue homeostasis.

Maternal one-carbon metabolism, MTHFR and TCN2 genotypes and neural tube defects in India.

BACKGROUND Neural tube defects (NTDs) are among the most common severe congenital malformations, representing a long-term public health burden in India. A deranged one-carbon metabolism and genes regulating this metabolism have been linked to NTDs. Vitamin B(12) deficiency is reported to be more prevalent than folate deficiency in the Indian population. We investigated the role of maternal nutritional and genetic markers related to one-carbon metabolism in the etiology of NTDs. METHODS We conducted a multicenter case-control study to compare plasma folate, vitamin B(12) , homocysteine and holo-transcobalamin levels, and polymorphisms in methylenetetrahydrofolate reductase (MTHFR, 677C>T, 1298A>C, 1781G>A and 236+724A>G) and transcobalamin (TCN2, 776C>G) genes, in 318 women with NTD-affected offspring (cases) and 702 women with apparently healthy offspring (controls). The samples were collected at diagnosis in cases and at delivery in controls. RESULTS We observed a significant association of high maternal plasma homocysteine concentrations with NTDs in the offspring (p = 0.026). There was no association of maternal folate or B(12) levels with NTDs (p > 0.05) but low maternal holo-transcobalamin predicted strong risk of NTDs in the offspring (p = 0.003). The commonly associated maternal polymorphism 677C>T in the MTHFR gene did not predict risk of NTDs in the offspring (p > 0.05) and 1298A>C and 1781G>A polymorphisms in MTHFR were protective (p = 0.024 and 0.0004 respectively). Maternal 776C>G polymorphism in TCN2 was strongly predictive of NTD in the offspring (p = 0.006). CONCLUSION Our study has demonstrated a possible role for maternal B(12) deficiency in the etiology of NTDs in India over and above the well-established role of folate deficiency.

A Novel Syndrome of Mandibular Hypoplasia, Deafness, and Progeroid Features Associated with Lipodystrophy, Undescended Testes, and Male Hypogonadism

CONTEXT Mandibuloacral dysplasia (MAD) is an autosomal recessive progeroid disorder associated with type A (partial) or B (generalized) lipodystrophy and is due to mutations in lamin A/C (LMNA) or zinc metalloproteinase (ZMPSTE24) genes. OBJECTIVE The objective of the study was to report a novel syndrome with some overlapping features with MAD. RESULTS We report seven patients with mandibular hypoplasia, deafness, progeroid features (MDP), and associated lipodystrophy. These patients have similar features to MAD patients such as hypoplastic mandible, beaked nose, stiff joints, and sclerodermatous skin. However, the patients did not harbor any disease causing variants in LMNA or ZMPSTE24 and showed distinct characteristics such as sensorineural hearing loss and absence of clavicular hypoplasia and acroosteolysis. All males with MDP had undescended testes and were hypogonadal. One adult female showed lack of breast development. Skinfold thickness, dual-energy X-ray absorptiometry and whole-body magnetic resonance imaging for body fat distribution revealed a lack of lipodystrophy in a prepubertal female but a progressive loss of sc fat presenting with partial lipodystrophy in young adults and generalized lipodystrophy in older patients. CONCLUSIONS Patients with MDP syndrome have a few overlapping but some distinct clinical features as compared with MAD, suggesting that it is a novel syndrome. The molecular basis of MDP syndrome remains to be elucidated.

Burden of Lysosomal Storage Disorders in India: Experience of 387 Affected Children from a Single Diagnostic Facility

Lysosomal storage disorders (LSDs) are considered to be a rare metabolic disease for the national health forum, clinicians, and scientists. This study aimed to know the prevalence of different LSDs, their geographical variation, and burden on the society. It included 1,110 children from January 2002 to December 2012, having coarse facial features, hepatomegaly or hepatosplenomegaly, skeletal dysplasia, neuroregression, leukodystrophy, developmental delay, cerebral-cerebellar atrophy, and abnormal ophthalmic findings. All subjects were screened for I-cell disease, glycolipid storage disorders (Niemann-Pick disease A/B, Gaucher), and mucopolysaccharide disorders followed by confirmatory lysosomal enzymes study from leucocytes and/or fibroblasts. Niemann-Pick disease-C (NPC) was confirmed by fibroblasts study using filipin stain. Various storage disorders were detected in 387 children (34.8 %) with highest prevalence of glycolipid storage disorders in 48 %, followed by mucopolysaccharide disorders in 22 % and defective sulfatide degradation in 14 % of the children. Less common defects were glycogen degradation defect and protein degradation defect in 5 % each, lysosomal trafficking protein defect in 4 %, and transport defect in 3 % of the patients. This study demonstrates higher incidence of Gaucher disease (16 %) followed by GM2 gangliosidosis that includes Tay-Sachs disease (10 %) and Sandhoff disease (7.8 %) and mucopolysaccharide disorders among all LSDs. Nearly 30 % of the affected children were born to consanguineous parents and this was higher (72 %) in children with Batten disease. Our study also demonstrates two common mutations c.1277_1278insTATC in 14.28 % (4/28) and c.964G>T (p.D322Y) in 10.7 % (3/28) for Tay-Sachs disease in addition to the earlier reported c.1385A>T (p.E462V) mutation in 21.42 % (6/28).

Fetal programming of type 2 diabetes : Is sex important?

Hales and Barker (1) caused a paradigm shift in our thinking about diabetes prevention when they demonstrated that low birth weight (due to growth retardation) predicted type 2 diabetes (the “thrifty phenotype” or “fetal origins” hypothesis). On the other hand, larger babies of diabetic mothers are also at higher risk of diabetes, apart from their genetic susceptibility (“fuel mediated teratogenesis”) (2,3). A concept evolved that the intrauterine experiences mold the fetal systems (“programming”) and influence future health (4). If the postnatal experiences are at variance with the intrauterine ones, the programmed fetus is susceptible to disease (5). For example, low birth weight babies who put on excess weight in later life are at a higher risk of type 2 diabetes than those who continue to be low weight (6). In the programming hypothesis, the focus is on the role of intrauterine environment and on gene-environment interaction rather than the differences in gene structure, which are the basis of conventional genetics. Genes are clearly important, and their role in intrauterine development and risk of diabetes was highlighted by Hattersley and Tooke (the “fetal insulin hypothesis”) (7). The most exciting thought in fetal programming is that intrauterine environment may modify gene expression permanently. A heritable change in gene expression without a change in DNA sequence is called “epigenetic” (8), a term first used by Waddington in developmental biology. Epigenetic changes alter gene function and can be silencing …

Lysosomal Storage Disorders in Nonimmune Hydrops Fetalis (NIHF): An Indian Experience

Lysosomal storage disorders (LSD) are rare inherited neurovisceral inborn errors of metabolism which may present as nonimmune hydrops fetalis (NIHF) during pregnancy. Although causes of NIHF are highly diverse, LSDs are one of the underlying causes of NIHF. The aim of this study was to elucidate most frequent causes of LSDs presenting as NIHF in Indian population. Several fetal tissues were investigated for enzymatic diagnosis of LSDs using modified fluorometric assays in the current prospective study carried out at our national tertiary center from 2006 through 2016. Other general causes of NIHF were ruled out. Twenty-one percent (7/33) of cases were confirmed to have LSDs. Two patients were diagnosed with Hurler syndrome; two had Sly syndrome and one each of Niemann-Pick disease type A/B, Gauchers disease, and mucolipidosis. Four of eleven cases (36%) with recurrent NIHF were found to have LSDs. In spite of extreme rarity of LSDs, they should be considered as a potential cause of NIHF, especially with recurrent NIHF. Specific investigations of LSD leading to definitive diagnosis may aid the clinician in providing accurate genetic counseling and prenatal diagnosis to the patients and help in subsequent pregnancies to the families. Furthermore, early intervention and management with enzyme replacement therapy may be planned for the lysosomal storage disorders where available.

Diagnostic utility of array-based Comparative Genomic Hybridization in a clinical setting

Background Submicroscopic genomic imbalances are a major cause of congenital and developmental abnormalities including unexplained Developmental Delay (DD), Intellectual Disability (ID), Autism Spectrum Disorders (ASD) and Multiple Congenital Anomalies (MCA). Submicroscopic imbalances are not visible at the resolution level offered by conventional cytogenetics techniques but could potentially be analysed with array based comparative genomic hybridization (aCGH) which offers high resolution scan of the genome. We present the motion backed by clinical evidence for the diagnostic utility of aCGH in a clinical settings for aforementioned cases.