Disease relevance of TNDM

• Transient neonatal diabetes mellitus (TNDM) is a rare inherited diabetic syndrome apparent in the first weeks of life and again during early adulthood [1].
• Neonatal hyperglycemia occurs only on paternal transmission, analogous to paternal dependence of TNDM in humans [1].
• Transient neonatal diabetes mellitus (TNDM) is associated with intra-uterine growth retardation, dehydration and a lack of insulin [2].
• Our findings further strengthen the hypothesis that ZAC is the gene responsible for TNDM and suggest a novel mechanism for ZAC inactivation in breast tumors [3].
• Maturity onset diabetes of the young (MODY) and early onset Type II diabetes are not caused by loss of imprinting at the transient neonatal diabetes (TNDM) locus [4].

High impact information on TNDM

• Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM [1].
• The inheritance pattern of this imprinted disorder implicates overexpression of one or both genes within the TNDM locus: ZAC, which encodes a proapoptotic zinc finger protein, and HYMAI, which encodes an untranslated mRNA [1].
• Functional characterization of the TNDM associated mutations was performed by expressing the mutated Kir6.2 with SUR1 in Xenopus laevis oocytes [5].
• We identified the three novel heterozygous mutations (G53S, G53R, I182V) in three of 11 probands with clinically defined TNDM, who did not have chromosome 6q24 abnormalities [5].
• Finally, we provide in vivo evidence that in the majority of TNDM patients with a normal karyotype, there is a loss of methylation within the highly homologous region [2].

Chemical compound and disease context of TNDM

• The article presents a case study describing an episode of hyperglycemia that could have been TNDM or an exaggerated response to the use of dexamethasone [6].

Biological context of TNDM

• Transient neonatal diabetes mellitus (TNDM) is associated with overexpression of an imprinted locus on chromosome 6q24; this locus contains a differentially methylated region (DMR) consisting of an imprinted CpG island that normally allows expression only from the paternal allele of genes under its control [7].
• The method is therefore capable of detecting all known genetic causes of TNDM at 6q24, although pUPD6 and methylation mutation cases are not distinguished from one another [7].
• We have also shown that TNDM is associated with both paternal uniparental disomy (UPD) of chromosome 6 and paternal duplications of the critical region [8].
• In addition, two patients with TNDM, in whom neither paternal UPD of chromosome 6 nor duplication of 6q24 have been found, show a DNA methylation pattern identical to that of patients with paternal UPD of chromosome 6 [8].
• TNDM is known to result from upregulation of a paternally expressed gene on chromosome 6q24 [9].

Anatomical context of TNDM

• We describe a screen for new imprinted human genes, and the identification in this way of ZAC (zinc finger protein which regulates apoptosis and cell cycle arrest)/ PLAGL1 (pleomorphicadenoma of the salivary gland gene like 1) as a strong candidate gene for transient neonatal diabetes mellitus (TNDM) [9].
• The pattern of inheritance of TNDM and its association with chromosome 6 uniparental disomy is consistent with the presence on chromosome 6 of an imprinted gene involved in pancreatic beta-cell development [10].
• The other patient, currently 12 years old, had a normal birth weight but showed impaired post-natal growth; in addition to TNDM the patient presented with cardiac and thyroid abnormalities [11].
• In TNDM fibroblasts, the monoallelic expression of both ZAC and HYMAI is relaxed, providing strong supportive evidence that the presence of two unmethylated alleles of this locus is indeed associated with the inappropriate gene expression of neighbouring genes [12].

Regulatory relationships of TNDM

• Transient neonatal diabetes mellitus (TNDM) is a rare disease believed to result from overexpression of a paternally expressed gene controlled by a differentially methylated CpG island on chromosome 6q24 [12].

Other interactions of TNDM

• Three types of abnormality involving 6q24 are known to cause TNDM: paternal uniparental disomy of chromosome 6 (pUPD6), an isolated methylation defect of the imprinted CpG island at chromosome 6q24 and a duplication of 6q24 of paternal origin [7].
• Bisulphite sequencing of the DMR has facilitated the development of a diagnostic test for TNDM based on ratiometric methylation-specific polymerase chain reaction [7].
• We investigated whether mutations in KCNJ11 could also give rise to TNDM [5].
• No excess of HLA susceptibility markers for type 1 diabetes (IDDM) was observed in this series of patients, whatever the forms of diabetes PNDM or TNDM [13].

Analytical, diagnostic and therapeutic context of TNDM

• However, TNDM was considered in differential diagnosis because he was small for gestational age (SGA) at birth and his symptoms had started at the 25th day of the neonatal period [14].

References