Homozygous and heterozygous expression of a novel mutation of the acid-labile subunit.
BACKGROUND
Acid-labile subunit (ALS) deficiency due to homozygous inactivation of the ALS gene (IGFALS) is associated with moderate short stature, and in few cases pubertal delay. The clinical expression of heterozygosity is unknown.


OBJECTIVE
To investigate the clinical, laboratory, and radiological features of homozygous and heterozygous carriers of a novel mutation in the ALS gene in comparison with non-carriers.


METHODS
Three short Kurdish brothers and their relatives.


RESULTS
The index cases presented with short stature, microcephaly, and low circulating IGF-I and IGF-binding protein-3 (IGFBP-3), and undetectable ALS levels. Two were known with a low bone mineral density and one of them had suffered from two fractures. We found a novel homozygous ALS gene mutation resulting in a premature stop codon (c.1490dupT, p.Leu497PhefsX40). The IGF-I, IGFBP-3, and ALS 150 kDa ternary complex was absent, and ALS proteins in serum were not detected with western blot. IGFPB-1 and IGFPB-2 were low and there was a mild insulin resistance. Five heterozygous carriers tended to have a lower height and head circumference than five non-carriers, and had low plasma ALS and IGFBP-3 levels. Bone mineral (apparent) density was low in two out of three homozygous carriers, and also in four out of nine relatives.


CONCLUSIONS
The clinical presentation of homozygous ALS mutations may, besides short stature, include microcephaly. Heterozygous carriers may have less statural and head growth, suggestive for a gene dosage effect.
van Duyvenvoorde
H A
HA
Departments of Paediatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. h.a.van_duyvenvoorde@lumc.nl
Kempers
M J E
MJ
Twickler
Th B
TB
van Doorn
J
J
Gerver
W J
WJ
Noordam
C
C
Losekoot
M
M
Karperien
M
M
Wit
J M
JM
Hermus
A R M M
AR
D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004392:Dwarfism / Q000150:complications / Q000235:genetics*; D005190:Family; D005260:Female; D006023:Glycoproteins / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008831:Microcephaly / Q000150:complications / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype
D002352:Carrier Proteins; D006023:Glycoproteins; C075944:insulin-like growth factor binding protein, acid labile subunit