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.
Endocrinology and Diabetes Research Group, Hospital de Cruces, Barakaldo, 48903 Spain.
Intza
I
Garin
Emma L
EL
Edghill
Ildem
I
Akerman
Oscar
O
Rubio-Cabezas
Itxaso
I
Rica
Jonathan M
JM
Locke
Miguel Angel
MA
Maestro
Adnan
A
Alshaikh
Ruveyde
R
Bundak
Gabriel
G
del Castillo
Asma
A
Deeb
Dorothee
D
Deiss
Juan M
JM
Fernandez
Koumudi
K
Godbole
Khalid
K
Hussain
Michele
M
O'Connell
Thomasz
T
Klupa
Stanislava
S
Kolouskova
Fauzia
F
Mohsin
Kusiel
K
Perlman
Zdenek
Z
Sumnik
Jose M
JM
Rial
Estibaliz
E
Ugarte
Thiruvengadam
T
Vasanthi
Karen
K
Johnstone
Sarah E
SE
Flanagan
Rosa
R
Martínez
Carlos
C
Castaño
Ann-Marie
AM
Patch
Eduardo
E
Fernández-Rebollo
Klemens
K
Raile
Noel
N
Morgan
Lorna W
LW
Harries
Luis
L
Castaño
Sian
S
Ellard
Jorge
J
Ferrer
Guiomar
G
Perez de Nanclares
Andrew T
AT
Hattersley
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