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DIABETES MELLITUS, TRANSIENT NEONATAL, 1
Alternative titles; symbols
TNDM1
TNDM
DMTN
Gene map locus 6q24, 6q24, 6q24
TEXT
One form of transient neonatal diabetes (TNDM1) has been linked to alterations
in an imprinted region of 6q24 that includes the PLAGL1 (603044) and HYMAI
(606546) genes. Another form (TNDM2; 610374) is caused by mutation in the ABCC8
gene (600509) on chromosome 11p15.1. A third form (TNDM3; 610582) is caused by
mutation in the KCNJ11 gene (600937), also located on 11p15.1.
Neonatal diabetes mellitus (NDM), defined as insulin-requiring hyperglycemia
within the first month of life, is a rare entity, with an estimated incidence of
1 in 400,000 neonates (Shield, 2000). In about half of the neonates, diabetes is
transient and resolves at a median age of 3 months, whereas the rest have a
permanent form of diabetes (606176). In a significant number of patients with
transient neonatal diabetes mellitus, type II diabetes appears later in life
(Arthur et al., 1997).
Temple et al. (1996) reviewed the manifestations of transient neonatal diabetes
mellitus (TNDM) and the evidence for an imprinted, paternally expressed gene on
chromosome 6q22-q23. They reported that TNDM occurs with a frequency of
approximately 1 in 500,000 births. Patients are born with intrauterine growth
retardation and present within the first 6 weeks of life with severe failure to
thrive, hyperglycemia and dehydration. Temple et al. (1996) noted that there is
evidence for failure of insulin (176730) production in response to glucose
feeding and that insulin therapy is usually required. The condition usually
resolves within the first 6 months of life. However there is a predisposition
toward type 2 (insulin resistant) diabetes (see 601283) later in life. Temple et
al. (1996) reported a family with a duplication in the 6q22-6q23 region
associated with TNDM. Another family with TNDM showed linkage to D6S310, a
marker in the 6q22-q23 region.
Hurst and McVean (1997) examined the conflict theory for the evolution of
genomic imprinting. The theory proposes that imprinting is an intraindividual
manifestation of classic parent-offspring conflict. The theory predicts that
imprinted genes expressed from the paternally derived genome should be enhancers
of pre- and postnatal growth, while those expressed from the maternally derived
genome should be growth suppressors. Hurst and McVean (1997) examined this
prediction by reviewing the literature on growth of human and mouse progeny that
inherited both copies (or part thereof) of a particular chromosome from only 1
parent. They found that much of the data do not support the conflict theory
hypothesis. They pointed to paternal uniparental disomy of chromosome 6 (UPD6),
which is associated with severe growth retardation. The conflict theory would
suggest that growth should be enhanced. In their Figure 1, they illustrated the
patient reported by Ferguson and Milner (1970).
The association between TNDM and either paternal isodisomy or duplication of
6q22-q23 raised the possibility of an imprinted gene in this location. Arthur et
al. (1997) reported diabetes that developed in a baby girl immediately after
birth and resolved after 7 weeks of insulin treatment. Because of her relatively
coarse facial features and a protruding tongue, cytogenetic analysis was
performed, showing an inverted duplication of 6q: invdup(6)(q22q23). The
duplicated segment was located between DNA loci D6S308 and D6S1684. Arthur et
al. (1997) concluded that the patient findings supported the assumption that an
imprinted gene exists on 6q22-q23. The duplication in the patient reported by
Arthur et al. (1997) was of paternal origin and spans the same region as that in
a family reported by Temple et al. (1996).
Gardner et al. (1998) analyzed samples from their cohort of patients with
transient neonatal diabetes mellitus by uniparental disomy of chromosome 6 using
polymorphic microsatellite repeat analysis. They reported the fifth case of
paternal uniparental disomy of chromosome 6 associated with classic transient
neonatal diabetes mellitus and estimated that uniparental disomy of chromosome 6
accounts for approximately one-fifth of cases of this syndrome.
Christian et al. (1999) reported 2 patients who presented at birth with neonatal
diabetes mellitus: one with paternal uniparental disomy for chromosome 6 and one
with normal, biparental inheritance. The first child presented with low birth
weight, macroglossia, hypertelorism, and clubfoot in addition to NDM. In this
patient hyperglycemia was transient, and insulin treatment was discontinued at 4
months of age. The second child also presented with low birth weight but was
normal in appearance, and insulin dependence continued after 5 years. Genetic
analysis with polymorphic DNA markers for chromosome 6 indicated the presence of
paternal uniparental disomy in the first case and normal, biparental inheritance
in the second case. Christian et al. (1999) found reports of 8 previous cases of
UPD6 of which 6 showed NDM. Three cases with paternal UPD6 also included
additional anomalies, such as macroglossia, not usually associated with NDM.
Christian et al. (1999) suggested, therefore, that the simultaneous finding of
NDM and macroglossia should be a strong indicator for genetic testing. The
genetic finding of paternal UPD6 allows prediction of a transient, rather than a
permanent, form of diabetes mellitus and no increased recurrence risk of
transient NDM in subsequent pregnancies.
Gardner et al. (1999) refined the previously defined critical region in
transient NDM to a region of 6q24 defined by markers D6S1699 and D6S1010, within
an interval of approximately 5.4 Mb. By further sequencing, Gardner et al.
(2000) refined the region to a 300 to 400 kb region which contains several CpG
islands. At one island, they noted differential DNA methylation between patients
with paternal UPD of chromosome 6 and normal controls. In addition, 2 patients
with TNDM, in whom neither paternal UPD of chromosome 6 nor duplication of 6q24
had been found, showed a DNA methylation pattern identical to that of patients
with paternal UPD of chromosome 6. Control individuals showed a hemizygous
methylation pattern. The authors concluded that TNDM can be associated with a
methylation change and that there is a novel methylation imprint on chromosome 6
associated with TNDM.
Since either duplication of a portion of chromosome 6q or uniparental disomy
have been associated with transient neonatal diabetes mellitus, overexpression
of an imprinted gene in this disorder is suggested. Prior to the report by Das
et al. (2000), all patients with transient neonatal diabetes mellitus and
uniparental disomy had had complete paternal isodisomy. Das et al. (2000)
described a patient with neonatal diabetes, macroglossia, and craniofacial
abnormalities who had partial paternal uniparental disomy of chromosome 6
involving the distal portion of 6q (6q24-qter). This observation demonstrated
that mitotic recombination of chromosome 6 can also give rise to uniparental
disomy and neonatal diabetes, a situation similar to that observed in Beckwith-Wiedemann
syndrome (BWS; 130650), another imprinted disorder.
Marquis et al. (2000) described 2 patients who suffered from transient neonatal
diabetes mellitus due to paternal isodisomy of chromosome 6. One patient, 5
years old at the time of report, had severe intrauterine growth retardation, but
recovered normal growth parameters. The other patient, 12 years old at the time
of report, had a normal birth weight but showed impaired postnatal growth; in
addition to TNDM, this patient presented with cardiac and thyroid abnormalities.
Arima et al. (2001) showed that the differentially methylated CpG island that
partially overlaps Zac1 (PLAGL1; 603044) and Hymai (606546) at the mouse locus
syntenic for 6q24 is a likely imprinting control region (ICR) for the 120- to
200-kb domain. The region is unmethylated in sperm but probably methylated in
oocytes, a difference that persists between parental alleles throughout pre- and
postimplantation development. Within this ICR, there is a region that exhibits a
high degree of homology between mouse and human and acts as a strong
transcriptional repressor when methylated. In 5 of 6 TNDM patients studied with
a normal karyotype, loss of methylation at 8 CpG sites within the region was
demonstrated. ZAC/PLAGL1 is a transcriptional regulator of the type 1 receptor
for pituitary adenylate cyclase-activating polypeptide (102981), potent known
insulin secretagogue and an important mediator of autocrine control of insulin
secretion in the pancreatic islet. The authors proposed that the ICR adjacent to
ZAC may regulate expression of imprinted genes within the domain, and that
epigenetic or genetic mutations of this region probably result in TNDM by
affecting expression of ZAC in the pancreas and/or the pituitary.
Temple and Shield (2002) reviewed TNDM as a disorder of imprinting. They noted
that 3 genetic mechanisms had been shown to result in TNDM: paternal uniparental
isodisomy of chromosome 6, paternally inherited duplication of 6q24, and a
methylation defect at a CpG island overlapping exon 1 of ZAC/HYMAI.
Bisulphite sequencing of the differentially methylated region (DMR) of 6q24
facilitated development of a diagnostic test for TNDM based on ratiometric
methylation-specific PCR. Mackay et al. (2005) applied this method to 45 cases
of TNDM, including 12 with paternal UPD6, 11 with an isolated methylation
mutation at 6q24, 16 with a duplication of 6q24, and 6 of unknown etiology,
together with 29 normal controls. All were correctly assigned.
Kant et al. (2005) reported female monochorionic, triamniotic, monozygous
triplets, 2 of whom had TNDM. Methylation-specific PCR showed that the 2
affected children had isolated loss of maternal methylation within the TNDM DMR;
the third unaffected child had normal PCR results. The discordant phenotype in 2
of 3 triplets suggested that the imprinting error may have preceded twinning in
this case.
Mackay et al. (2006) reported 2 unrelated TNDM patients who had loss of maternal
methylation both at 6q24 and at the centromeric DMR on 11p15.5 (KCNQ1OT1;
604115), which is involved in imprinting abnormalities in Beckwith-Wiedemann
syndrome. Both patients presented with intrauterine growth retardation and TNDM
without features of overgrowth. However, both had moderate macroglossia and
abdominal wall defects, features occasionally found in both BWS and TNDM.
Mackay et al. (2006) performed DNA methylation analysis on a cohort of 12
patients with TNDM and total loss of maternal methylation on 6q24. Six of these
patients showed a spectrum of methylation loss that was mosaic with respect to
the extent of the methylation loss, the tissues affected, and the genetic loci
involved. These patients had higher birth weight and were more phenotypically
diverse than other TNDM patients, presumably reflecting the influence of
dysregulation of multiple imprinted genes. Mackay et al. (2006) proposed the
existence of a maternal hypomethylation syndrome and suggested that any patient
with methylation loss at 1 maternally-methylated locus might also manifest
methylation loss at other loci, potentially complicating or even confounding the
clinical presentation.
Diatloff-Zito et al. (2007) reported a group of 13 sporadic transient neonatal
diabetes cases, including 5 with birth defects (congenital abnormalities of
heart, brain, and bone) and 8 without. Two of the patients had paternal
uniparental disomy-6 (UPD6); of the remaining 11 cases, 2 had complete and 3 had
partial loss of the maternal methylation signature upstream of the ZAC1-HYMAI
imprinted genes in non-UPD cases. There was 1 case of hemizygous deletion among
all 13 cases, in a patient with severe congenital malformations. Diatloff-Zito
et al. (2007) raised the hypothesis that the deletion had an effect on
regulatory elements critical for imprinting and tissue-specific gene expression
in early development.
ANIMAL MODEL
The inheritance pattern of transient neonatal diabetes mellitus implicates
overexpression of 1 or both genes within the TNDM locus: ZAC (603044), which
encodes a proapoptotic zinc finger protein, and HYMAI (606546), which encodes an
untranslated mRNA. To investigate the consequences for pancreatic function, Ma
et al. (2004) developed a high-copy transgenic mouse line carrying the human
TNDM locus. Neonates of this line displayed hyperglycemia, and older adults,
glucose intolerance. Neonatal hyperglycemia occurred only on paternal
transmission, analogous to paternal dependence of TNDM in humans. The embryonic
pancreata of these mice showed reductions in expression of endocrine
differentiation factors and numbers of insulin-staining structures. By contrast,
beta-cell mass was normal or elevated at all postnatal stages, whereas
pancreatic insulin content in neonates and peak serum insulin levels after
glucose infusion in adults were reduced. Expression of human ZAC and HYMAI in
these transgenic mice thus recapitulated key features of TNDM and implicated
impaired development of the endocrine pancreas and beta-cell function in disease
pathogenesis.
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