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.
Garin
Intza
I
Endocrinology and Diabetes Research Group, Hospital de Cruces, Barakaldo, 48903 Spain.
Edghill
Emma L
EL
Akerman
Ildem
I
Rubio-Cabezas
Oscar
O
Rica
Itxaso
I
Locke
Jonathan M
JM
Maestro
Miguel Angel
MA
Alshaikh
Adnan
A
Bundak
Ruveyde
R
del Castillo
Gabriel
G
Deeb
Asma
A
Deiss
Dorothee
D
Fernandez
Juan M
JM
Godbole
Koumudi
K
Hussain
Khalid
K
O'Connell
Michele
M
Klupa
Thomasz
T
Kolouskova
Stanislava
S
Mohsin
Fauzia
F
Perlman
Kusiel
K
Sumnik
Zdenek
Z
Rial
Jose M
JM
Ugarte
Estibaliz
E
Vasanthi
Thiruvengadam
T
Johnstone
Karen
K
Flanagan
Sarah E
SE
Martínez
Rosa
R
Castaño
Carlos
C
Patch
Ann-Marie
AM
Fernández-Rebollo
Eduardo
E
Raile
Klemens
K
Morgan
Noel
N
Harries
Lorna W
LW
Castaño
Luis
L
Ellard
Sian
S
Ferrer
Jorge
J
Perez de Nanclares
Guiomar
G
Hattersley
Andrew T
AT
D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics*; D018628:Gene Dosage; D005808:Genes, Recessive / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D015345:Oligonucleotide Probes; D011498:Protein Precursors / Q000235:genetics*
D017931:DNA Primers; D007328:Insulin; D015345:Oligonucleotide Probes; D011498:Protein Precursors; C013737:preproinsulin