Novel compound heterozygous mutations of ALDH1A3 contribute to anophthalmia in a non-consanguineous Chinese family

Abstract

Anophthalmia is a rare eye development anomaly resulting in absent ocular globes or tissue in the orbit since birth. Here, we investigated a newborn with bilateral anophthalmia in a Chinese family. Exome sequencing revealed that compound heterozygous mutations c.287G > A (p.(Arg96His)) and c.709G > A (p.(Gly237Arg)) of the ALDH1A3 gene were present in the affected newborn. Both mutations were absent in all of the searched databases, including 10,000 in-house Chinese exome sequences, and these mutations were confirmed as having been transmitted from the parents. Comparative amino acid sequence analysis across distantly related species revealed that the residues at positions 96 and 234 were evolutionarily highly conserved. In silico analysis predicted these changes to be damaging, and in vitro expression analysis revealed that the mutated alleles were associated with decreased protein production and impaired tetrameric protein formation. This study firstly reported that compound heterozygous mutations of the ALDH1A3 gene can result in anophthalmia in humans, thus highlighting those heterozygous mutations in ALDH1A3 should be considered for molecular screening in anophthalmia, particularly in cases from families without consanguineous relationships.

Novel mutations in ALDH1A3 associated with autosomal recessive anophthalmia/microphthalmia, and review of the literature

“…The ALDH1A3 variant alleles identified in the NAD-binding domain, important for tetramer stabilization include Val71Met, Arg89Cys, Arg96His, Ala145Val, Cys174Tyr, Gly237Arg and Gly282Ala [6, 14–16, 19–21]. In the present study, a further novel variant (p.Glu58Glyfs*5) was identified in the NAD-binding domain.…”

“…Val71MetIsraeli9AMMory et al [15]c.265C > Tp. Arg89CysPakistani2AMFares-Taie et al [6]c.287G > Ap.Arg96HisChinese1ALiu et al [21]c.434C > Tp. Ala145ValSaudi Arabian2MAldahmesh et al [14]c.521G > Ap.Cys174TyrLebanese3AMRoos et al [16]c.709G > Ap.Gly237ArgChinese & Iranian3ALiu et al [21]; Dehghani et al [19]c.845G > Cp.Gly282AlaArabic2MAlabdullatif et al [20]c.964G > Ap.Val322MetIndian1AUllah et al [3]c.1064C > Gp.Pro355ArgEgyptian1AAbouzeid et al [17].…”

“…Among these families, 50 individuals are from consanguineous families [3, 5, 6, 13–19], one from a non-consanguineous family, [5] and three are sporadic or individual cases [5, 20]. Recently, Liu and coworkers identified compound heterozygous variants in ALDH1A3 in a proband from a non-consanguineous family with anophthalmia [21]. Among the reported ALDH1A3 -associated anophthalmia and microphthalmia cases, 30 have been demonstrated in families of Arab origin including families from Egypt [17], Saudi Arabia [14], Lebanan [16], Morocco [6], Israel [15], and the United Arab Emirates [20], 10 in families of Turkish origin [18], and 12 cases have been found in South and East Asian families including families from Pakistan [3, 6], Iran [19], India [3], Sri Lanka [17] and China [21].…”

“…Recently, Liu and coworkers identified compound heterozygous variants in ALDH1A3 in a proband from a non-consanguineous family with anophthalmia [21]. Among the reported ALDH1A3 -associated anophthalmia and microphthalmia cases, 30 have been demonstrated in families of Arab origin including families from Egypt [17], Saudi Arabia [14], Lebanan [16], Morocco [6], Israel [15], and the United Arab Emirates [20], 10 in families of Turkish origin [18], and 12 cases have been found in South and East Asian families including families from Pakistan [3, 6], Iran [19], India [3], Sri Lanka [17] and China [21]. Reported consanguinity rates are high (22–55%) in these populations, which has been associated with an increased risk of autosomal recessive diseases due to homozygosity of regional founder mutations [22].…”

“…In the present study, a further novel variant (p.Glu58Glyfs*5) was identified in the NAD-binding domain. These variants may impact on tetramer stability, with the newly synthesized unstable proteins predicted to be unstable and therefore subjected to proteasome-dependent degradation in the cells [6, 21]. The Cys174Tyr, Lys190*, Gly237Arg and Gly282Ala variants are located at the foot of the NAD-binding domain (Ile171- Gly282).…”